Physiol Rev 92: 1865–1913, 2012
doi:10.1152/physrev.00018.2011
ROLE OF ION CHANNELS AND TRANSPORTERS
IN CELL MIGRATION
Albrecht Schwab, Anke Fabian, Peter J. Hanley, and Christian Stock
Institut für Physiologie II, Münster, Germany
Schwab A, Fabian A, Hanley PJ, Stock C. Role of Ion Channels and Transporters in Cell
Migration. Physiol Rev 92: 1865–1913, 2012; doi:10.1152/physrev.00018.2011.—Cell
motility is central to tissue homeostasis in health and disease, and there is hardly any
cell in the body that is not motile at a given point in its life cycle. Important physiological
processes intimately related to the ability of the respective cells to migrate include
embryogenesis, immune defense, angiogenesis, and wound healing. On the other side, migration
is associated with life-threatening pathologies such as tumor metastases and atherosclerosis.
Research from the last ⬃15 years revealed that ion channels and transporters are indispensable
components of the cellular migration apparatus. After presenting general principles by which
transport proteins affect cell migration, we will discuss systematically the role of channels and
transporters involved in cell migration.
L
I.
II.
III.
IV.
V.
VI.
VII.
INTRODUCTION
MECHANISMS OF CELL MIGRATION
MECHANISMS BY WHICH ION...
CHANNELS INVOLVED IN CELL...
TRANSPORTERS INVOLVED IN CELL...
PHYSIOLOGY AND PATHOPHYSIOLOGY...
CONCLUSION AND OUTLOOK
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I. INTRODUCTION
Cell motility is central to tissue homeostasis in health and
disease. Thus there is hardly any cell in the body that is not
motile at a given point in its life cycle. After gastrulation cells
have to reach the sites within the embryo that give rise to the
different organs (11). Migration in the context of organ development and differentiation continues after birth. Neuroblasts
still need to move postnatally to their final “place of work”
within the brain (292, 293, 601). Migration of enterocytes
along the crypt-villus axis occurs throughout the entire lifespan
(651). Similarly, immune cells permanently patrol through our
body and defend it against invading pathogens (162, 414,
541). Already more than 150 years ago, Julius Cohnheim
described the concept of leukocyte diapedesis in great detail
in his classical paper on inflammation and suppuration [“Über
Entzündung und Eiterung” (98); commented on in Ref.
258; see also FIGURE 1, which is taken from a paper of one
of Cohnheim’s contemporaries (71)]. Wound healing of the
skin requires the movement of keratinocytes and fibroblasts
(362). Wounding also frequently affects the mucosa of the
gastrointestinal tract, and migration of epithelial cells into
the denuded area is a fast way to reestablish epithelial integrity (38, 127). Angiogenesis which is also triggered during wound healing is yet another example for a process
depending on migration (560).
The downside of migration is represented by disease conditions in which cell migration constitutes a major pathophysiological element. The most prominent example is the formation of tumor metastases. Tumor cell migration is an
essential step of the so-called metastatic cascade that leads
to the spread of the disease within the body (341, 639).
Rheumatoid arthritis and atherosclerosis are chronic inflammatory diseases involving the migration of leukocytes
as well as that of synovial fibroblasts (319, 459) and smooth
muscle cells, respectively (429, 576). These examples
clearly illlustrate the diversity of the physiological and
pathophysiological functions of migrating cells and highlight its medical importance.
The systematic study of cell migration goes back more than
150 years. First mechanistic models of amoeboid movement
were developed in the second half of the 19th century (reviewed in Refs. 366, 367). The old models focussed on what
was later to be defined as the cytoskeleton, which is one of
the major intracellular motors of cell migration (103, 315,
441, 464). It goes of course without saying that there has
been an enormous technical progress that can be illustrated
by comparing the image acquisition of migration experiments. While Mast and co-workers projected the cell under
observation with a camera lucida and made sketches of the
cells’ posterior ends in minute intervals (233), modern technologies allow frame rates of several thousand Herz, subpixel lateral resolution well below the refractive limit, or
intravital observation of migrating cells (72, 486).
However, one component of the cellular migration machinery, namely, transport proteins in the plasma membrane,
was largely neglected until quite recently. Studies from the
last ⬃15 years have unequivocally shown that the plasma
membrane (277) and the transport proteins inserted therein
0031-9333/12 Copyright © 2012 the American Physiological Society
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SCHWAB ET AL.
seen in the presence or absence of directional stimuli (181,
402, 480). The polarization applies to morphology and
function. This is particularly evident when cells are migrating on a two-dimensional substrate. Such conditions are
typical for epithelial cells during wound healing (38) or for
neutrophils adhering to the endothelium prior to transmigration (414, 449). The majority of cells, however, migrate
in a three-dimensional environment. The front part of migrating cells is formed by a fanlike, 300-nm-thin, and organelle-free process, the lamellipodium (2, 3). Cell body
and uropod form the rear part of the cell. Persistent migration is only possible when this polarization is maintained.
FIGURE 1. Historical hand drawing of the recruitment of neutrophil granulocytes through the vascular wall. Although the figure is
older than 140 years, the top small panels 1– 6 clearly present the
stages of rolling, diapedesis, and migration in the interstitial space.
[From Caton (71).]
also play important roles in cell migration. This will be the
main focus of our review. We will provide an overview of
mechanisms by which transport proteins contribute to the
process of cell migration, we will systematically discuss relevant transport proteins, and finally, we will integrate their
function in selected disease states.
II. MECHANISMS OF CELL MIGRATION
A. Common Properties of Migrating Cells
One of the common features of all migrating cells is their
polarization along their axis of movement, which can be
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The polarization of migrating cells applies to many different
aspects of the cellular migration apparatus. First of all, it
concerns the opposing movements of the front and rear cell
poles. Migration can be described as a repeated and highly
coordinated cycle of protrusion of the lamellipodium and
retraction of the rear part of the cell. Protrusion of the
anterior and retraction of posterior parts of migrating cells
requires that the respective components of the cellular migration machinery, e.g., polymerizing actin filaments at the
cell front and contractile proteins at the rear end, are differentially localized and regulated within a migrating cell. We
refer to recent reviews (103, 248, 315, 390, 464, 479) for a
detailed overview of cytoskeletal mechanisms of migration.
Force generated by the migration machinery must be transmitted onto the surrounding matrix so that the cell can
eventually advance. The turnover of the respective cell adhesion receptors requires a constant supply of “new” receptors being delivered to the cell front resulting in an asymmetric distribution of integrins in migrating cells (52, 264,
314, 630). Finally, the polarization of migrating cells also
comprises the subcellular distribution of other membrane
proteins such as chemokine receptors (354) and transport
proteins (see sects. III–V) as well as the composition of the
plasma membrane itself (602).
B. Cell-Matrix Interactions During
Cell Migration
Migration requires a coordinated formation and release of
focal adhesion contacts to transmit force developed by the
cellular migration motor to the underlying extracellular
matrix (50, 54). In most cells integrins are central components of focal adhesion contacts that are comprised of multiprotein complexes also containing the Na⫹/H⫹ exchanger
NHE1 (243, 453). Integrins are composed of different ␣
and ␤ subunits and serve as receptors for proteins of the
extracellular matrix. The subunit composition of integrins
determines their specificity for proteins of the extracellular
matrix. Integrins are also important “hubs” for transmitting signals in the outside-in and inside-out direction, since
they interact with a plethora of proteins on both sides of the
plasma membrane. The abundance and complexity of pro-
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
tein-protein interactions at these contact sites is reflected by
the term “adhesome” (655).
Importantly, cell adhesion turnover is also regulated by
ionic mechanisms. The contribution of Ca2⫹ and protons
has been studied in particular detail. The disassembly of
focal adhesion components at the rear part of migrating
cells involves the Ca2⫹-sensitive family of calpain proteases
(68, 74). The turnover of LFA-1 adhesions in migrating T
lymphocytes depends on calpain 2 activity. Inhibition or
knockdown of calpain 2 impairs the disassembly of LFA-1
adhesions so that T lymphocytes cannot detach their rear
part or become elongated, and LFA-1 is shed (567). The
gradient of the intracellular Ca2⫹ concentration ([Ca2⫹]i)
that has been found in many migrating cells including T
lymphocytes contributes to the localized diassembly of focal adhesions, since [Ca2⫹]i is usually higher at their rear
end than at their front (56, 95, 149, 202, 519, 625). Accordingly, calpain activity is highest in the rear part of T
lymphocytes (567).
The pH dependence of cell adhesion was revealed by applying force measurements with atomic force microscopy, cell
behavioral assays, and molecular dynamics simulations.
RGD peptides that constitute a typical recognition motif for
integrin binding of extracellular matrix proteins such as
fibronectin bind most firmly to ␣␯␤3 or ␣5␤1 integrins in the
plasma membrane of osteoclasts at pH 6.5 (321). Binding of
collagen I to ␣2␤1 integrins is pH dependent too. This was
deduced from biochemical assays with isolated proteins
(141) and from adhesion and migration experiments with
human melanoma (MV3) cells in which the effects of variations of the extracellular pH (pHe) were explored. Adhesion and migration of ␣2␤1 integrin-expressing melanoma
cells have their optimum at pHe 6.8 and pHe 7.0, respectively (299, 554, 558, 561). Such a behavior is also found in
␣␯␤3 integrin expressing CHO cells (436). Computational
molecular dynamics simulations revealed a possible molecular mechanism for these effects. The conformational equilibrium of ␣␯␤3 integrins and thereby their state of activation depends on pHe. An acidic extracellular environment
(pHe ⬍7.0) directly activates ␣␯␤3 integrins and increases
their ligand avidity by inducing a shift of their conformation towards the opening of the integrin headpiece (436).
Finally, there is a strong indirect or physical crosstalk between integrins and several K⫹ channels (e.g., KCa1.1,
KV1.3, and KV11.1). KCa1.1 channels in endothelial and
arteriolar smooth muscle cells are activated following ␣V␤3
or ␣5␤1 integrin binding to vitronectin or fibronectin in a
manner that involves a c-src-dependent tyrosine phosphorylation of the channel protein (274, 646). In lymphocytes,
tumor or neuronal cells ␤1 integrin and KV1.3 or KV11.1
channel impact on each other so that adhesion is regulated
by K⫹ channel activity (15, 20, 85, 325). Along the same
lines, KV2.1 channels contribute to the activation of FAK in
mesenchymal stem and corneal epithelial cells (239, 626)
while TRPM8 channels inactivate FAK in PC-3 prostate
carcinoma cells (647). In osteoblasts, the association of
KCa1.1 with FAK could be promoted by exposing cells to a
hyposmotic environment (477).
C. Chemotaxis
The directed migration towards (or away from) the source
of an extracellular signal molecule (chemoattractant) is
termed chemotaxis. The cells’ ability to detect and to respond to such directional clues is not only a prerequisite for
embryogenesis and the normal body homeostasis but also
for the development of pathological conditions such as the
formation of tumor metastases (504, 568, 639). The general
view is that chemotaxis of eukaryotic cells occurs by spatial
sensing. Cells detect concentration differences as small as
1% along their length axis, amplify them intracellularly,
and thereby elicit the cellular responses underlying directed
migration (504). The concentration differences of the chemoattractant will lead to a higher receptor occupancy at the
part of the cell facing the source of the chemoattractant
(245) resulting in asymmetrical stimulation of G proteincoupled chemoattractant receptors. This corresponds to the
local excitation/global inhibition model of chemotaxis that
produces a local membrane protrusion towards the chemoattractant source and retraction of the rear part of the
cell (568).
A major breakthrough in the field was the discovery that
activation of phosphoinositide 3-kinase (PI3K) via G proteins causes the accumulation of PI(3,4,5)P3 at the cell pole
facing the chemoattractant source (478) which is accentuated by the PI-3-phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) at the rear part of
chemotacting cells (166, 246). However, chemotactic gradient sensing does not solely rely on PI(3,4,5)P3 signaling,
since chemotaxis is possible even in the absence of polarized
PI(3,4,5)P3 and type 1 PI3Ks (228). A variety of redundant
chemotactic signaling pathways come into play when a cell
has to prioritize between diverging chemotaxis gradients
and needs to decide which path to take. This is reflected in
the concept that neutrophils favor bacterial chemoattractants
or complement components (“end-target chemoattractants”)
over chemokines (“intermediary chemoattractants”) with p38
MAPK and PI3K being the respective intracellular signaling
modules (154, 223, 224, 650).
An alternative model of chemotaxis suggests that it can
occur without spatial gradient sensing. Instead, cells generate membrane protrusions continually, and chemoattractants only cause biased extension of existing extensions towards the higher concentrations. Thus chemotactic gradients
rather modulate dynamics of already existing lamellipodia
than causing the appearance of new ones (13).
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Heterotrimeric G proteins usually belonging to the G␣i/o
family and monomeric G proteins (e.g., Rho, Rac, Cdc42)
are of central importance for chemotactic signal transduction. Pertussis toxin-sensitive members of the G␣i/o family
stimulate PI3K via the G␤␥ subunit. The resulting accumulation of PI(3,4,5)P3 accumulation and Rac activation contributes to the definition of the (new) front of the cell. Activation of G␣12/13 may provide “backness” through links
to RhoGEFs (Rho guanine nucleotide exchange factors),
which “turn on” Rho, required for retraction of the trailing
end (629, 634). We could show that myosin IXb may act as
RhoGAPs (GTPase-activating proteins) and selectively inhibit Rho at the leading edge of macrophages (210).
Activation of PLC-␤ isoforms and internal Ca2⫹ release are
other common features of chemotactic signaling, mediated
either through G␣q/11 or G␤␥ subunits from activated G␣i/o
(261). While it is established that chemoattractant stimulation frequently induces elevations of the intracellular Ca2⫹
concentration (112, 255), the molecular identity of the involved ion channels and their mechanisms of action are far
less understood. Thus it is not yet known whether the crucial role of autocrine purinergic signaling mediated by chemoattractant-induced ATP release for neutrophil (80) and
macrophage (301) chemotaxis is due to shaping intracellular Ca2⫹ signals. Some recent studies indicate that ion channels controlling the intracellular Ca2⫹ homeostasis are of
critical importance for efficient chemotaxis (23, 39, 148,
530, 538) or for the related process of nerve growth cone
steering (535, 536, 613, 628).
The Na⫹/H⫹ exchanger NHE1 is another transport protein
that is crucial for the polarization of migrating cells (118,
126, 524, 556). In ameobae (Dictyostelium discoideum), a
developmentally regulated NHE (DdNHE1) is needed for
cell polarity and for efficient chemotaxis in response to
cAMP. DdNHE1 is expressed only in chemotactically competent and not in vegetative cells, confirming its necessity
for directed movement (443).
III. MECHANISMS BY WHICH ION
TRANSPORT AFFECTS
CELL MIGRATION
Many of the general principles by which ion transport proteins regulate cell migration are related to the housekeeping
functions exerted by ion transport proteins such as setting
the cell membrane potential as well as regulating cell volume, [Ca2⫹]i, and intra- and extracellular pH. Since the cell
membrane potential and cell volume regulation involve
many functionally diverse families of ion channels and
transporters, their role in cell migration will be discussed in
the following sections to provide a more unified view. The
impact of [Ca2⫹]i and of pH on the cellular migration machinery will be discussed in detail as an introduction to the
sections on Ca2⫹ and pH regulatory transport proteins,
respectively (see sects. IVE and VA).
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There is accumulating evidence that the role of some ion transport proteins in cell migration can be attributed to their nonconductive properties that do not depend on the transport of
ions. They are either mediated by the ion-transporting protein
itself or by associated ancillary subunits (e.g., ␤-subunits of
voltage-gated Na⫹ channels or of the Na⫹-K⫹-ATPase).
Transport proteins have a large repertoire of nonconductive properties including but not limited to the combination of channel and enzymatic activity in one protein
(“chanzyme” TRPM2, -6, -7; Ref. 502), conformational
coupling to other proteins (450) or the function as a
signaling platform (330). In other cases, the nonconductive mechanisms have not yet been elucidated (627). Finally, ancillary units of transport proteins can even operate as adhesion receptors (14, 91, 444). We will refer to
these effects in more detail when discussing the individual transport proteins.
A. Cell Membrane Potential
The membrane potential of migrating cells serves the same
housekeeping and signaling functions like in any other eukaryotic cell. It indirectly affects cell migration by regulating cell volume as well as intra- and extracellular pH (see
sects. IIIB and VA). In addition, the cell membrane potential
plays a particularly important role in setting the electrical
driving force for Ca2⫹ influx and controlling the gating
behavior of voltage-dependent Ca2⫹ channels. Thus, in a
cell expressing voltage-independent Ca2⫹ channels (e.g.,
TRP channels), [Ca2⫹]i rises in response to a hyperpolarization, while in excitable cells expressing voltage-gated Ca2⫹
channels a rise of [Ca2⫹]i can be induced by a depolarization. Functional coupling with Ca2⫹-sensitive K⫹ channels
may then lead to a positive-feedback cycle promoting sustained Ca2⫹ influx (171) or to a negative feedback terminating Ca2⫹ influx (150), respectively. Along these lines, the
depolarizing effect of TRPM4 channel-mediated cation influx has been linked to attenuating Ca2⫹ influx in nonexcitable cells (310). The functional importance of the cell membrane potential for cell migration is elegantly illustrated in
neutrophils. In these cells, proton channels (VSOP/Hv1)
prevent the depolarization of the cell membrane potential
during respiratory burst and thereby sustain Ca2⫹ influx
required for cell migration. Consequently, neutrophils from
VSOP/Hv1⫺/⫺ mice have a strong defect in chemokinetic
migration (144).
In addition, a depolarization of the cell membrane potential
exerts a modulatory effect on the cytoskeleton (88, 571,
612). Thus, in renal epithelial cells, a depolarization activates a signaling cascade consisting of ERK ¡ GTP/GDP
exchange factor GEF-H1 ¡ Rho ¡ Rho-kinase leading to
myosin light chain phosphorylation (571, 612). In endothelial cells, the membrane potential is sensed by the cortical
actin network and determines the actin polymerization/depolymerization ratio and thus cell stiffness. A depolariza-
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
tion of the cell membrane potential softens endothelial cells
by depolymerizing the cortical actin cytoskeleton (62).
Since the plasma membrane is only 5 nm thin, the seemingly
small membrane potential of approximately ⫺50 mV
builds up an electric field of 107 V/m. Changes of this electrical field can, for example, control the conformation and
thereby the activity of membrane proteins such as voltagegated ion channels. The electric field across the plasma
membrane also promotes the interaction between KV11.1
channels with ␤1-integrins and the recruitment of further
signaling molecules such as FAK and Rac1 when the cell
membrane potential hyperpolarizes upon KV11.1 activation (424, 450).
Moreover, the activity of voltage-dependent enzymes such as
the phosphoinositide phosphatase Ci-VSP, a member of the
PTEN family of phosphatidylinositol phosphatases, is controlled by the membrane potential (254, 400). Depolarization
of the plasma membrane activates Ci-VSP and leads to cleavage of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and
thereby regulates the activity of PI(4,5)P2-dependent ion
channels. So far, it is not known whether Ci-VSP plays a
role in cell migration by regulating the PI(4,5)P2 supply for
the actin modulator cofilin (326) or for ion channels involved in cell migration. If this were the case, one would
expect a temporal correlation between protrusive lamellipodial activity and membrane potential oscillations frequently observed in migrating cells (209, 526, 527). In such
a scenario, a hyperpolarization of the cell membrane potential would shut down Ci-VSP, thereby increasing PI(4,5)P2
availability, which in turn would inhibit cofilin and protrusive activity at the leading edge. In this context, it is noteworthy that in Ciona intestinalis Ci-VSP is expressed in
NADPH oxidase (gp91)-positive blood cells which include
the highly motile phagocytes (419).
With the use of nanoparticles encapsulating voltage-sensitive fluorescent dyes, it was recently found that electric
fields extend far beyond the plasma membrane into the
cytosol (596). This raises the question whether there is a
functional crosstalk between the electric field generated
by the cell membrane and the electric fields originating
from intracellular organelles (234) or macromolecular
complexes (461, 595). At this stage, the relative contribution and tissue specificity of indirect housekeeping effects, of membrane-delimited processes such as Ci-VSP
mediated PI(4,5)P2 cleavage, or of long-range electric
field effects in controling cell migration is still an open
issue.
B. Cell Volume
Cell migration can be described as a repetitive cycle of protrusion of the cell front that is followed by retraction of the
rear part. In terms of cell volume, this cycle can be modeled
as volume gain at the cell front and volume loss at the rear
part of migrating cells (see FIGURE 2). Such a view is also
supported by the frequent observation that the protrusion
of the lamellipodium and the retraction of the rear part do
not always occur simultaneously in migrating cells. Rather,
one of these processes temporarily dominates so that the cell
volume rises during the protrusion of the lamellipodium,
whereas it decreases during the retraction of the rear part.
Such (local) volume changes of up to 35% have been visualized and quantified in migrating cells using atomic force
(515), scanning ion conductance (211), or multiphoton laser scanning fluorescence microscopy (620). Neutrophil
granulocytes increase their volume upon chemotactic but
not upon chemokinetic stimulation. When this gain of volume is prevented by exposing neutrophils to a hypertonic
solution, chemotaxis is inhibited. Accordingly, neutrophils
emigrated into inflamed lung tissue or into the abdominal
wall have a larger cell volume than intravascular ones (490,
631).
That volume changes remain restricted to one cell pole can
be attributed at least partially to the poroelastic structure of
the actin meshwork and cytoplasm within the lamellipodium. It is able to resist osmotic water flow, thereby preventing or retarding the immediate equalization of local
volume changes (77, 251, 252, 386). Moreover, the stiffness of the lamellipodium gradually increases towards the
leading edge so that the cell body is softer and more easily
deformable than the lamellipodium (311, 463). In addition,
the lamellipodium is attached more firmly to the substratum
than the cell body (153, 515). These properties prevent the
lamellipodium from decreasing its volume to the same extent as the cell body upon concomitant K⫹ and Cl⫺ channel
activation and restrict the volume loss to the rear part of
migrating cells. Local volume changes can thereby “mechanically” support protrusion and retraction of front and
rear parts of migrating cells, respectively. When cells are
migrating through a tortuous three-dimensional extracellular matrix, volume changes may also be required to overcome narrows (200, 470, 549, 581, 620).
A specialized form of localized volume change in migrating
cells is represented by the phenomenon of “blebbing.” It is
commonly explained on the basis of a contraction of the
actomyosin network that causes an increase of the intracellular hydrostatic pressure. Local weakening of the cortical
cytoskeleton allows the cytosol to be squeezed into the rapidly forming blebs of the plasma membrane. That is, blebbing is explained as a consequence of intracellular volume
shifts. However, for the following reasons, we propose that
transport of solutes and water across the plasma membrane
contributes to the expansion of blebs as well. The poroelastic nature of the cytoskeleton impairs the immediate equalization of local volume changes (77, 386), and ion transport
proteins including aquaporins are in the “correct” subcellular position to allow rapid solute and water uptake from
the extracellular space (118, 119, 197, 200, 287, 492, 497,
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ENaC
NHE1
Na+
Na+
Na+
K+
2Cl–
Cl–
Actin
NKCC1
AE2
H2O
AQP 1,4
VRAC
CIC3
KCa3.1
MscCa
Protrusion
Ca2+
Cl–
K+
H2O
Retraction
FIGURE 2. Cell volume changes during cell migration. Cell migration is a continuous cycle of protrusion of the
cell front and retraction of the trailing end. This can be modeled as a cycle of isosmotic volume increase at the
cell front and isomotic volume decrease at the rear end. This model is based on direct measurements of
volume changes in migrating cells (211, 515, 620) and on the subcellular distribution of the relevant ion
transport proteins and aquaporins. The molecular nature of the mechanosensitive Ca2⫹ channels implicated
in this model is still elusive. The scheme illustrates how members of the “transportome” cooperate during cell
migration.
556). Finally, aquaporins are found in the plasma membrane of blebs (242), and increasing the extracellular osmolarity inhibits bleb formation (653).
Cell volume regulation critically depends on the activity of
ion channels and transporters (see Ref. 229 for a current
comprehensive review). Practically all cells return to their
normal volume following an osmotic perturbation by either
activating K⫹ and Cl⫺ channels and releasing KCl and cell
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water (regulatory volume decrease, RVD) or by activation
of Na⫹-K⫹-2Cl⫺ cotransport, Na⫹/H⫹ exchange, and nonselective cation channels leading to the net uptake of KCl
and water (regulatory volume increase, RVI). Employing
the terminology of volume regulation, cell migration can
then be described as a cycle of isosmotic RVI at the cell front
and RVD at the rear part. Accordingly, many of the ion
channels and transporters participating in cell volume regulation are part of the cellular migration machinery. Exam-
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
ples include KCa3.1 (105, 508, 527, 530), VRAC (357,
513), KV1.3 (368), various TRP channels (617, 625),
NHE1 (118, 217, 287, 481, 554), NKCC1 (200, 475, 527),
or aquaporins (435) to name just a few. A quantitative
evaluation of NHE1-mediated Na⫹ fluxes in MDCK-F cells
revealed that it is of a magnitude sufficient to contribute to
lamellipodial protrusion (287).
The above-mentioned volume model of cell migration requires the concerted, interdependent activity of a whole set
of channels and transporters that belong to many different
families of transport proteins. To account for this complexity, we would like to introduce the concept of a migrationasociated “transportome”. This concept implies that it is
not the isloated function of a single ion channel or transporter but rather the activity of a whole network of transport proteins that is required for efficient migration. It appears that some transportome members such as aquaporins,
KCa3.1, or NHE1 are found in most migrating cells, while
others like proton channels (144) are expressed cell-type
specifically so that the transportome meets the special needs
of a given cell (see sects. IV and V for a detailed discussion
of these transport proteins).
IV. ION CHANNELS INVOLVED
IN CELL MIGRATION
In the following section we will systematically summarize
the current state-of-the-art concerning the contribution of
molecularly defined ion channels to the cellular migration
machinery. We will limit our discussion to the most relevant
channels. This discussion is complemented by TABLE 1 listing the channels found to be involved in cell migration.
When indicated we will also refer to studies investigating
the role of transport proteins in the movement of nerve
growth cones, which is a process closely related to cell migration.
A. Kⴙ Channels
K⫹ channels form the largest family of ion channels with
more than 70 members in mammals (http://www.iuphar-db.
org/). They were among the first transport proteins that
were recognized to play a crucial role in cell migration (17,
18, 527). Their role in cell migration was the topic of a
recent review (521) that will be updated in this section.
1. Voltage-gated K⫹ channels
The link between cell volume regulation and cell migration becomes more evident when considering the rapid
and pronounced polymerization and depolymerization of
the actin cytoskeleton following osmotic shrinkage and
osmotic swelling, respectively (204, 265, 447, 482, 525).
Volume-dependent modulation of the actin cytoskeleton
also concerns the activity and subcellular localization of
proteins associated with actin filaments such as the myosin light chain (121), myosin II (447), cortactin (123),
and the ERM protein ezrin (474). Hence, by setting the
“correct” cell volume, ion channels and transporters
have an important impact on the organization of the
actin cytoskeleton. Intermediaries between cell volume
perturbations and the actin cytoskeleton include Rho,
Rac, Cdc42, and PI(4,5)P2, which are highly sensitive to
cell volume changes and which constitute important signaling modules in the control of actin dynamics (122,
123, 286, 335, 407, 425, 474, 652). Importantly,
PI(4,5)P2 also regulates the activity of many ion channels
and transporters involved in cell migration (340) such as
KV1.3 (49, 325), TRPC1 and -6 (39, 78, 109, 149, 205,
346), TRPV1 (617), TRPM4 (23, 408), TRPM7 (495),
NHE1 (8, 558), and NCX1 (134, 648). Moreover, many
studies have shown that ion channels and transporters
involved in volume regulation and cell migration are regulated by the actin cytoskeleton and associated proteins
(198, 230, 265, 286, 323, 370, 371, 373, 411). Such
findings lend strong support to the concept of a mutual
interdependence of ion channel and transporter function,
cell volume regulation, and cytoskeletal dynamics during
cell migration.
KV1.3, KV10.1, and KV11.1 channels are the best studied
voltage-gated K⫹ channels in the context of cell migration.
They are of particular importance for cells of the immune
system and for tumor cells where they constitute potential
therapeutic, diagnostic, and/or prognostic targets (see also
sect. VI, A and B).
A) KV1.
KV1.1 channels are reported to play a role in wound
healing of intestinal and gastric epithelial cells (472, 540,
615). The effect of KV1.1 channels on migration of these
epithelial cells is ascribed to setting the electrochemical
driving force for Ca2⫹ influx and subsequently triggering
Ca2⫹-dependent RhoA signaling. KV1.1 expression itself is
regulated by intracellular polyamine synthesis.
However, most studies on the role of KV1 channels in cell
migration are focused on KV1.3 channels (20, 175, 282,
325, 368, 416, 610). Blockade or reduced expression of
KV1.3 channels is invariably followed by an inhibition of
migration. This is of particular physiological relevance for
the immune system since KV1.3 channels play a crucial role
in orchestrating the immune response (59). Migration of
effector memory T lymphocytes (368) or macrophages
(175, 610) depends on KV1.3 function. Migration of alveolar macrophages is also inhibited by KV1.5 knockdown
(440). The almost complete inhibition of migration of effector memory T lymphocytes in a model of delayed-type
hypersensitivity by a specific KV1.3 blocker was explained
on the basis of suppressed Ca2⫹ signaling leading to insufficient integrin activation (368). Possibly, this “housekeeping” effect of KV1.3, controlling [Ca2⫹]i (see sect. IIIA), is
Physiol Rev • VOL 92 • OCTOBER 2012 • www.prv.org
1871
SCHWAB ET AL.
Table 1. Ion and water channels involved in cell migration
Channel
Cell Type
Function in Cell Migration
Reference Nos.
K⫹ channels
KV1.1
intestinal epithelial cells
KV1.3
gastric epithelial cells
lymphocytes
melanoma cells
neutrophil granulocytes
vascular smooth muscle cells
KV1.5
KV2.1
alveolar macrophages
CHO cells, corneal epithelial cells
bone marrow mesenchymal stem cells
KV3.1
KV7.1
oligodendrocyte progenitor cell
chicken neuroblasts
embryonic Xenopus melanocytes
alveolar epithelial cells
KV10.1
KV11.1
acute myeloid leukemia cells
melanoma cells
acute myeloid leukemia cells
neuroblastoma cells
KCa1.1
colon cancer cells
zebrafish neutrophils
glioma cells
KCa2.3
melanoma cells
breast cancer cells
mouse colon epithelial cells
neuronal progenitor cells
KCa3.1
MDCK-F cells
MDCK cells
fibroblasts
bronchial epithelial cells
melanoma cells
microglia
1872
expression elevates [Ca2⫹]i and accelerates
wound closure
accelerates wound closure
cell adhesion, coimmunoprecipitates with
integrins
interacts with ␤1-integrins of adhering
melanoma cells
detection of electric fields and their
coupling to metabolic oscillators
blockade inhibits migration and neointima
formation
knockdown inhibits migration
promotes migration and wound closure by
interacting with FAK
promotes FAK activation and thereby stem
cell migration and homing to injured
tissue
block or knockout inhibit migration
blockade inhibits migration
increases melanocyte migration by
hyperpolarization-dependent activation of
transcription factors Sox10 and Slug
blockade with clofilium delays epithelial
wound healing
inhibition impairs migration
knockdown inhibits migration
confers promigratory phenotype to AML
blasts
inhibition prevents neurite outgrowth,
regulates integrin signaling
modulates colon cancer cell invasiveness
knockdown impairs neutrophil recruitment
blockade or activation inhibit migration;
leads to CaMKII-dependent migration
after ionizing irradiation
enhances motility by hyperpolarizing the cell
membrane potential
knockdown inhibits migration
expression correlates with motility
channel activation induces filopodia
formation
blockade slows down, induces local
reduction of cell volume at the rear part,
activation dampens lamellipodial
dynamics, required for chemokinetic
stimulation with FGF-2
blockade slows down
blockade slows down and induces actin
depolymerization
delayed epithelial restitution upon inhibition,
part of EGF signaling cascade
blockade slows down
blockade slows down, prevents
chemokinetic stimulation
Physiol Rev • VOL 92 • OCTOBER 2012 • www.prv.org
472, 615
540
325
20
282
84b
440
626
239
585
227
398
592
6
5
451
17, 19, 85
308
55
40, 298, 553, 621
76
455, 457
458
334
279, 520, 525, 527,
528
263
106, 523
593
523
508
ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
Table 1.—Continued
Channel
Cell Type
macrophages
monocytes
lung dendritic cells
platelets
vascular smooth muscle cells
osteoclasts
glioblastoma cells
HEK293
Kir4.2
MEFs, CHO & glioma cells
Function in Cell Migration
knock-out/blockade inhibits chemoaxis,
contributes to atherosclerosis in vivo
blockade inhibits chemotaxis towards
MCP-1
activation elevates [Ca2⫹]i and inhibition
impairs chemotaxis towards
CC19/CCL21
required for SDF-1 stimulated migration
knock-out/blockade inhibits migration,
contributes to atherosclerosis in vivo
channel activity temporally correlated with
cell spreading
contributes to chemotactic response to
CXCL12; inhibition blunts migratory
response of U87-MG cells to FCS
heterologous expression accelerates
migration
colocalization with ␣9␤1 integrins and
spermidine/spermine acetyltransferase
(SSAT) increases persistence of
migration
Reference Nos.
590
506
533
509
84a, 564, 578, 590
146
70, 530
528
115, 604
Voltage-gated Na⫹ channels
Nav1.2, 1.6, 1.7
neoplastic mesothelial cells
microglia
macrophages
CD1a⫹ dendritic cells
NaV1.5
breast cancer
prostate carcinoma cells
T-lymphocytes
promotes motility
NaV1.6 required for ATP-induced migration
promotes formation of podosomes and
invasion
silencing hyperpolarizes cell membrane
potential and decreases migration
enhances motility, blockade eliminates
basal and PKA-stimulated cellular
migration
promotes motility and metastases
promotes invasion
165
36
69
285
47, 158
160, 401
159
ENaC/ASIC
ENaC
vascular smooth muscle cells
glioblastoma cells
BeWo cells
ASIC1
ASIC 1, 3
ASIC 2
astrocytes, glioblastoma cells
vascular smooth muscle cells
vascular smooth muscle cells
inhibition and siRNA impair migration
knockdown impairs migration
inhibition and knockdown mitigate
aldosterone-induced stimulation of
migration
enhances motility
siRNA impairs migration
reduced cell surface expression by heat
shock protein 70 stimulates migration
135
268
116
268, 608
193
193
Cl⫺ channels
VRAC
glioma cells
monocytes
NIH3T3 fibroblasts
CFTR
bronchial epithelial cells
ClC3
neutrophil granulocytes
cell shrinkage enhances invasive capacity
regulate transendothelial migration and
chemotaxis
increased volume sensitivity in rastransformed fibroblasts correlates with
increased migratory activity
contributes to epithelial wound healing by
regulating lamellipodial protrusion
blockade and knock-out inhibits
transendothelial migration, chemotaxis
and shape change during chemotaxis
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470, 549
280
513
505
396, 611
1873
SCHWAB ET AL.
Table 1.—Continued
Channel
Cell Type
Function in Cell Migration
glioma cells
HeLa cells
nasopharyngeal carcinoma cells
Xenopus laevis embryo
CLIC1
endothelial cells
TMEM16A /
ANO1
GABAC receptor
head and neck carcinoma cells
cortical interneurons
Reference Nos.
internalization inhibits migration, regulated
by CaMKII
knockdown imparis migration
blockade impairs migration
increased expression at wound edge,
blockade impairs wound healing
required for angiogenesis and migration
regulated by actin in planar lipid bilayers
overexpression stimulates migration
107, 376
promote or inhibit migration depending on
KCC2 expression
43, 120, 220, 452
356
355, 357, 358
163
544, 594
22
Mechanosensitive Ca2⫹ channels
keratinocytes
activation induces retraction of the rear
part
blockade at cell front inhibits migration and
traction force generation
fibroblasts
317
399
TRP channels
TRPC1
intestinal epithelial cells
neutrophil granulocytes
MDCK-F cells
endothelial cells
myoblast
Xenopus spinal neurons
Gn11 neuronal cells
TRPC5
vascular smooth muscle cells
endothelial cells
podocytes
hippocampal neurons
TRPC6
microvascular endothelial cells
aortic endothelial cells
neutrophils
eosinophils
TRPV1
glioblastoma cells
hepatoblastoma cells
corneal epithelial cells
F11 neuroblastoma x DRG neuron hybrid
cells; DRG neurons
1874
accelerates epithelial restitution, activity
enhanced by STIM1
electric field detection
cell polarity, persistent migration and
chemotaxis towards FGF-2
required for zebrafish angiogenesis
contributes to myoblast migration by
activating calpain and subsequent
proteolysis of MARCKS
guidance of nerve growth cones
suppresses migration by decreasing Ca2⫹
permeability of TRPC1-TRPC5
heteromers
required for stimulation of migration with
S1P or oxidized phospholipids
inhibits migration when translocated to the
plasma membrane
promotes cell migration via Rac1 activation
promotes axon formation and limits neurite
extension
involved in VEGF-stimulated migration,
sprouting, angiogensis; associates with
PTEN
LPC-induced inhibition of migration by
recruiting TRPC5 to plasma membrane
contributes to MIP-2 induced chemokinetic
migration
knockout leads to reduced bronchioalveolar
eosinophilia in allergic airway response
knockdown inhibits invasion
accelerates migration
stimulates migration via transactivation of
EGFR
COOH terminus interacts with ␤-tubulin,
activation induces disassembly of
microtubules and growth cone retraction
Physiol Rev • VOL 92 • OCTOBER 2012 • www.prv.org
471, 473
282
148, 149
654
346
329, 535, 536, 628
559
9, 636
78
583
111, 191
172, 205, 284
78
109
531
90
617
643
184–186
ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
Table 1.—Continued
Channel
Cell Type
TRPV2
prostate carcinoma cells
murine macrophages
TtT/M87 murine macrophage
TRPV4
hepatoblastoma cells
endothelial cells
Function in Cell Migration
breast cancer derived endothelial cells
TRPM2
neuroendocrine cells (GN11)
F11 neuroblastoma x DRG neuron hybrid
cells
monocytes/ neutrophils
dendritic cells
TRPM4
mast cells
dendritic cells
T lymphocytes
TRPM7
fibroblasts
HEK293 cells
HEK293, N1E-115, PC12, RBL,COS
cells
osteoblasts
vascular smooth muscle cells
nasopharyngeal carcinoma cells
A549 non-small cell lung cancer cells
Xenopus laevis embryos
pancreatic cancer cells
promotes migration
contributes to migration and chemotaxis
fMLP induces translocation to the cell
membane, required for chemotaxis
accelerates migration
ultra-fast activation upon mechanical
stimulation of ␤1-integrins; mediate
reorientation upon cyclic strain
mediates arachidonic acid stimulated
migration
activation inhibits migration and chemotaxis
activation leads to growth cone retraction;
interacts with actin and microtubuli
neutrophil chemotaxis towards fMLP and
indirectly by controlling ROS-induced
chemokine production in monocytes
mediates Ca2⫹ release from lysosomes
that is required for chemotaxis
involved in migration by regulation of Ca2⫹dependent actin rearrangements
chemokine-induced migration, impaired
migration to draining lymph nodes
inTRPM4⫺/⫺ mice
promotes/impairs motility of Th2/Th1
lymphocyte, respectively
Ca2⫹ flickers at leading edge control
directionality; required for polarized cell
movement, knockdown rescued by Mg2⫹
transporter
cell adhesion via calpain
cell adhesion via actomyosin; regulates
myosin IIA filament stability
involved in PDGF-induced migration
regulates bradykinin-induced migration
supports migration by mediating Ca2⫹ influx
EGF-mediated upregulation leads to
enhanced migratory activity
TRPM7 required for gastrulation,
knockdown rescued by Mg2⫹ transporter
knockdown inhibits migration, rescued by
extracellular Mg2⫹
Reference Nos.
393, 394
337
403
617
369, 580
152
656
187, 469
365, 640
565
538
23
624
563, 625
562
96, 97
1
61
79
169
339
496
ORAI/STIM
Orai1/STIM1
vascular smooth muscle cells
endothelial cells
neutrophils
T cells
breast cancer cells
cervical cancer cells
knockdown impairs migration, upregulated
in injured vessels
contributes to VEGF-induced chemotaxis
and angiogenesis
required for intravascular adhesion,
migration and mechanotransduction
knockout leads to impaired chemotaxis
knockdown inhibits migration by impairing
focal adhesion turnover
knockdown inhibits migration by impairing
focal adhesion turnover
35, 456
327
130, 501
349
645
81
P2X receptors
P2X1
neutrophils
enhances fMLP and IL-8 induced
chemotaxis
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316
1875
SCHWAB ET AL.
Table 1.—Continued
Channel
Cell Type
P2X4
microglia
P2X7
breast cancer
Function in Cell Migration
involved in chemotaxis and morphineinduced migration
enhances KCa2.3 channel and cathepsindependent cancer cell invasion
Reference Nos.
235, 421
259
Proton channel
VSOP/Hv1
maintains Ca2⫹ influx required for cell
migration by preventing membrane
potential depolarization
neutrophils
144
Aquaporins
AQP1
endothelial cells
proximal tubule epithelial cells
melanoma cells
gastric epithelial cells
corneal keratocytes
AQP3
AQP4
chondrocytes
glioma cells
gastric adeno-carcinoma cells
skin keratinocytes
skin fibroblasts
corneal epithelial cells
astroglial cells
adult neural stem cells
AQP5
human lung adenocarcinoma cells
AQP7
dendritic cells
AQP9
neutrophil granulocytes
fibroblasts
reinforced by its physical interaction and conformational
coupling with ␤1 integrins, i.e., by a nonconductive property of KV1.3 channels (20, 325). Voltage-dependent gating
of KV1.3 activates ␤1-integrins. Consequently, KV1.3 channel blockers prevent integrin activation.
These voltage-gated K⫹
channels will be discussed together since they share a medically important property. They are regulators of tumor cell
proliferation and migration, and upregulated expression of
KV10.1 and KV11.1 channels in many tumor cells is negaB) KV10.1 (EAG1) AND KV11.1 (ERG1).
1876
supports tumor angiogenesis and
angiogenesis in liver fibrosis enhances
lamellipodial protrusive activity and
blebbing
accelerates epithelial restitution
knock-down inhibits migration,
overexpression enhances migration and
tumor cell extravasation and metastases,
interacts wti Lin-7/␤-catenin
knock-down inhibits formation of
lamellipodia and migration
contributes to migration in vitro and during
wound healing in vivo
knock-out impairs migration and adhesion
enhances migration
contributes to EGF-stimulated cell migration
knock-down impairs migration and skin
wound healing
involved in EGF-induced migration
delayed epithelial restitution in knockout mice
promotes glial scar formation, enhances
lamellipodial protrusive activity
knock-out impairs migration by altering
intracellular Ca2⫹ signaling
knockdown reduces migration and invasion,
expression correlates with metastatic
potential
reduced chemotaxis and accumulation of
antigen-retaining dendritic cells in lymph
nodes
enhances lamellipodial protrusive activity,
promotes polarization following fMLP
stimulation
induces formation of filopodia
242, 497
213
238, 395
218
492
331
374
241
214
63
322
21, 498
294
73, 83
212
270, 342
343
tively correlated with patient prognosis (5, 6, 182, 308,
309, 432, 451). KV11.1 channels have similar nonconductive properties as KV1.3 channel in that they also form
complexes with ␤1-integrins in which both proteins reciprocally activate each other, presumably by conformational
coupling (reviewed in Ref. 450). KV11.1 channels are activated upon integrin-mediated adhesion to fibronectin or
laminin (17, 19), and integrin signaling depends on KV11.1
channel activity (85). Functionally, KV11.1 channels strongly
affect neurite outgrowth in neuroblastoma cells (17, 19) and
cell migration by controlling cell-matrix interactions and
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
IbTx
120
migration (% of control)
downstream signaling cascades. KV11.1 channels form a macromolecular signaling complex with the vascular endothelial
growth factor receptor-1, FLT-1, and ␤1-integrins in acute
myeloid leukemia (AML) cells. ␤1-Integrins mostly recruit the
KV11.1B isoform. This interaction is required for FLT-1 signaling activation and AML cell migration (in vitro and in vivo)
both of which are inhibited when KV11.1 channels are
blocked. Importantly, the FLT-1/KV11.1/integrin complex is
found in primary AML blasts from patients, too, and KV11.1
expression in leukemia patients correlates with a higher probability of relapse and shorter survival periods (451).
con
100
80
60
Ba2+
40
TEA
CTX
20
4-AP
0
r2 = 0.96
KV10.1 and KV11.1 channels also regulate the migration of
nontumorous cells. Thus KV10.1 contributes to the migration of rat cerebellar granule cells (338). In the zebrafish
model, KV11.1 antisense RNA morpholinos and pharmacological inhibitors attenuate neutrophil recruitment in response to an infectious stimulus (55).
2. Ca2⫹-sensitive K⫹ channels (KCa 3.1, KCa1.1,
KCa2.3)
Ca2⫹-sensitive K⫹ channels are divided into three groups:
KCa1.1 (formerly designated as BK), KCa2.1–2.3 (SK1–3),
and KCa3.1 (IK, SK4, or Gardos channel). They are all
involved in cell migration, with KCa3.1 channels being studied the most extensively. The important role of KCa3.1
channels in cell migration is underscored by their expression profile. They are expressed in virtually all migrating
cells including most immune cells (49, 59, 105, 136, 137,
171, 209, 508, 533, 590), platelets (509), osteoclasts (146),
vascular cells (51, 84, 289, 564, 578, 590), fibroblasts (106,
523), and several model cell lines used to study cell migration (70, 263, 279, 527, 528). Moreover, KCa3.1 channels
are stage-dependently (over-)expressed in tumors pointing
to a possible role in the metastatic cascade (216, 257, 306,
422, 431, 510, 523, 573, 616). In most cases, inhibition or
genetic deletion of KCa channels results in reduced migratory activity and impaired chemoaxis (see FIGURE 3). Conversely, increased expression of KCa3.1 channels frequently
correlates with increased migratory activity (528, 533,
564). The contribution to migration of different calciumsensitive K⫹ channels is cell type specific. KCa1.1 channels,
for example, are expressed in glioma and microglial cells.
Yet, they only modulate migration of glioma cells but not
that of microglia (298, 508, 553, 621).
The Ca2⫹ sensitivity of Ca2⫹-activated K⫹ channels couples
their activity to other Ca2⫹-dependent events during the
process of cell migration (see sect. IVE). Their activity follows spatial gradients and temporal fluctuations of [Ca2⫹]i
so that they are generally more active at the rear part than at
the front of migrating cells (520, 527, 528) and exhibit an
oscillating activity (146, 526). Consequently, topical application of the KCa3.1 channel blocker charybdotoxin inhibits migration only when it is directed towards the rear part
0
20
40
60
80
100
120
KCa3.1 channel activity (% of control)
FIGURE 3. Dependence of MDCK-F cell migration on the activity of
KCa3.1 channels. Blocking KCa3.1 channels with various K⫹ channel
inhibitors leads to a proportionate decrease of KCa3.1 channel activity and migration. [Adapted from Schwab et al. (527).]
of migrating MDCK-F cells (520). It is important for migrating cells that KCa channel activity is able to fluctuate
because tonic pharmacological KCa channel activation impairs migration (298, 525). Transient elevations of [Ca2⫹]i
preceding rear end retraction (317) trigger bursts of KCa
channel activity and K⫹ efflux (110). The resulting local
volume loss at the rear end (515) acts in concert with cytoskeletal Ca2⫹-dependent mechanisms underlying rear end
retraction such as actomyosin contraction or calpain-mediated integrin release. An alternative view is that in glioma
cells KCa channel-mediated volume loss predominantly affects invadopodia, thereby facilitating the invasion of the
narrow extracellular space of brain tissue (376, 620). KCa
channel-mediated volume changes are most likely accomplished by their parallel operation with volume-regulated
anion channels (VRAC) (357, 358, 513) or ClC3 channels
(376, 620) so that the combined application of KCa3.1 and
Cl⫺ channel blocker leads to an almost complete inhibition
of migration (70). In melanoma cells, additional KCa3.1
channel-dependent mechanisms support rear end retraction. By increasing [Ca2⫹]i (see below and sect. IIIA) KCa3.1
channels drive the secretion of the so-called melanoma inhibitory activity (MIA) at the rear part of the cells (510)
leading to facilitated cell detachment (25).
So far, it is not yet known which function KCa3.1 channels
exert at the cell front (528). They could serve a similar role
as in a secretory epithelium and recycle K⫹ taken up by the
Na⫹-K⫹-2Cl⫺ cotransporter NKCC1 which is concentrated at the front of migrating cells (200). Alternatively,
maximal activation of KCa3.1 channels in the vicinity of a
chemoattractant source could act synergistically with chemokine receptor internalization (489) to bring migration to a
stop at a focus of inflammation. This view is supported by
the observation that KCa3.1 channel activation at the cell
front slows down migrating cells (522, 528).
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SCHWAB ET AL.
In nonexcitable cells, KCa3.1 and KCa2 channels are involved in a positive feedback loop controlling the intracellular Ca2⫹ concentration (see sect. IIIA) (267, 306). This
relation to [Ca2⫹]i was proposed to account for the promigratory effect of KCa2.3 channels in breast cancer, melanoma, and colon epithelial cells. [Ca2⫹]i and migratory activity are correlated with the level of KCa2.3 channel expression (76, 455, 457). KCa2.3 expresion itself is controlled by
the adenomatous polyposis gene (Apc) in colonic epithelial
cells (458). In monocytes, the feedback between KCa channels and [Ca2⫹i] was elucidated a step further by identifying
TRPC6 and TRPV1 channels as being of equal importance
for chemotaxis as KCa3.1 channels (506, 507). In line with
the concept of the transportome, it is therefore conceivable
that TRPC6 and TRPV1 channels locally cooperate with
KCa3.1 channels by supplying the latter with Ca2⫹ needed
for their activation.
In addition to the above-mentioned mechanisms related to
their transport function, KCa channels also regulate migration by directly interacting with important molecular modules of the cellular migration apparatus such as FAK (477),
cortactin (584), or integrins (␣5␤1 or ␣V␤3) (274, 633).
Finally, there is a growing body of evidence that KCa3.1
channels are also part of growth factor/chemokine signaling
cascades so that inhibition of the channels prevents the
stimulation of migration by these agents (105, 279, 508,
530, 533).
3. Inwardly rectifying K⫹ channels
A) KIR4.2. Kir4.2 channels are regulated by intracellular polyamines such as spermine or spermidine that block outward
current through the channel. With the use of MEFs, CHO,
or glioma cells, it was shown that the association of ␣9␤1
integrins with spermidine/spermine acetyltransferase (SSAT)
links migration to the activity of Kir4.2 channels (115, 604).
Kir4.2 channels are colocalized with ␣9␤1 integrins at the
leading edge of the lamellipodium. This also places the polyamine catabolizing enzyme SSAT in the proximity of the
channel and thereby weakens its inward rectification and
allows (locally) more K⫹ efflux. A detailed analysis of the
migratory behavior of ␣9␤1 integrin and Kir4.2 expressing
cells revealed a pronounced increase of migratory persistence. It was suggested that locally enhanced K⫹ efflux promotes the formation of a single dominant lamellipodium
while at the same time preventing the formation of additional protrusions (115). These findings provide an instructive example for the importance of the local and spatially
restricted regulation of ion channels in cell migration.
B. Voltage-Gated Naⴙ Channels
At first sight it seems counterintuitive that voltage-gated
Na⫹ channels (NaV) can have any function in nonexcitable
1878
peripheral migrating cells. However, careful electrophysiological analysis of NaV channel currents in breast cancer
cells revealed that there is indeed sustained NaV1.5 activity
(“window current”) at membrane voltages between ⫺60
and ⫺20 mV. This is a voltage range typically encountered
in migrating cells (176). Moreover, NaV1.7 expression in a
subset of dendritic cells resulted in a depolarized cell membrane potential (285).
The first description of NaV channel expression in small-cell
lung cancer cells dates back more than 30 years (434). It
took a few years, however, to recognize that the expression
of NaV channels correlates with metastatic potential, i.e.,
cellular motility/invasiveness (196, 546). Initially, a transient tetrodotoxin-sensitive Na⫹ current was found only in
strongly metastatic Mat-Ly-Lu rat prostate cancer cells while
it was absent in any of the corresponding weakly metastatic
AT-2 cells (196). Transfection of a NaV (NaV1.4) into a
weakly invasive human prostate cancer cell line significantly increased its invasiveness (31). In the meantime,
the importance of NaV channels for the metastatic behavior
has been confirmed for many different tumor cells. Inhibition
of NaV (using TTX, siRNA, polyclonal antibodies) impairs
motility and invasive behavior (see FIGURE 4) (47, 125, 158,
165, 170, 307, 426, 484, 485). In addition, NaV channels
also contribute to cell motility and invasion of a number of
different immune cells such as lymphocytes (159), macrophages (69), microglia (36), and dendritic cells (285).
Importantly, NaV channels expressed in metastatic tumor
cells were found to be fetal splice variants, as seen clearly in
the case of NaV1.5 in human breast cancer cell (158). This
issue is consistent with the epigenetic nature of cancer and
oncofetal gene expression. To the best of our knowledge
there is only one report showing association of a NaV mutation with glioblastoma (266). The clinical potential of
neonatal NaV1.5 expression in human breast cancer was
discussed earlier (see Ref. 427 for review).
Several mechanisms contribute to NaV’s positive impact on
cell migration and invasion (see Ref. 48 for a recent review).
NaV1.5 promotes breast cancer cell invasion in a cysteine
cathepsin-dependent manner by inducing a pericellular
acidification (53, 176). In macrophages and melanoma
cells, intracellularly localized NaV1.6 supports the formation of podosomes and invadopodia, respectively, by causing shifts of intracellular Na⫹ and Ca2⫹ and thereby affecting signaling pathways that link intracellular NaV activation to actin cytoskeleton dynamics (69). NaV channels also
regulate migration in a nonconductive way by their associated ␤-subunits that act as cell adhesion molecules (46, 91,
113). In cerebellar granule neurons, ␣- and ␤1-subunits of
NaV channels assemble to macromolecular complexes with
contactin, and initiate a signaling cascade through fyn kinase leading to neurite outgrowth and migration (48). In
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
A
C
100
(i)
200
Control
Motility (%)
80
60
**
-200
200
40
-200
20
0
(ii)
CON
200
TTX
B
-200
200
100
+
Invasion (%)
-
-200
(iii)
80
200
TTX
***
60
-200
200
40
+
0
-200
-
(x and y axes = µm)
20
CON
TTX
FIGURE 4. Involvement of NaV channels in motility/invasion of
metastatic MDA-MB-231 breast cancer cells. The NaV channel
blocker tetrodotoxin (10 ␮M, TTX) inhibits motility in a transwell
assay (A), Matrigel invasion (B), and migration in an electric field of
3 V/cm (C). C depicts cell trajectories that are normalized to a
common starting point. Cell migration was monitored i) under control conditions in the absence of an electric field, ii) in the presence
of an electric field (3 V/cm), and iii) in the combined presence of an
electric field (3 V/cm) and the NaV blocker tetrodotoxin. The ability
of the cells to respond to the electric field is largely attenuated when
NaV channels are blocked. [Modified from Fraser et al. (158), by
permission of the American Association for Cancer Research.]
oligodendrocyte precursor (NG2) cells NaV channels contribute to GABA-promoted migration by inducing a sustained elevation of [Na⫹]i which in turn is responsible for
causing a Na⫹/Ca2⫹ exchanger (NCX)-mediated increase
of [Ca2⫹]i (589). Finally, functional expression of NaVs is
highly dynamic and under the control of a range of regulatory mechanisms, including growth factors (129, 599). On
the other hand, NaV1.5 activity itself is a high level regulator controlling the transcription of gene networks involved
in colon cancer invasion such as those of cell migration
(236).
C. ENaC/ASIC
In contrast to the widely accepted view that NaV channels
importantly contribute to tumor cell migration/invasion
data on the involvement of the epithelial Na⫹ channel
ENaC and on acid-sensing ion chanels (ACICs) in cell migration are still sparse. ENaC inhibition or knockdown impairs the migration of vascular smooth muscle (192), trophoblastic (BeWo) (116), corneal endothelial (88), glioma
cells (268), and neurite growth in PC12 cells (135). Con-
versely, the mineralocorticoid hormone aldosterone, which
promotes ENaC transcription, accelerates “wound” closure in scratch assays in an ENaC-dependent way. In BeWo
cells, ENaC is more abundant at the wound edge (116).
This is consistent with the observation that the cell membrane potential of corneal endothelial cells is more depolarized at the wound edge (88). This ENaC-mediated depolarization of the cell membrane potential was proposed to
stimulate cell migration by triggering actin cable formation
at the wound edge. Alternatively, ENaC could accelerate
migration by producing a local volume gain at the cell front,
since it is localized at the leading edge of the lamellipodium.
Acid-sensing ion channels (ASICs) belong to the same superfamily of cation channels as ENaC (275). Their proton
sensitivity could make them attractive signaling molecules
for adapting the behavior of tumor cells to their acidic environment (603). Indeed, enhanced expression of ASIC2a
and -3 was found in adenoid cystic carcinoma tissue
(649). However, so far a role of ASIC1, -2, and -3 in cell
migration has only been demonstrated in astrocytes, glioblastoma (268, 608, 609), and smooth muscle cells
(192, 193). The common result of these studies is that
ASIC2 is a negative regulator of migration in astrocytes
or A10 vascular smooth muscle cells by suppressing a
voltage-independent, amiloride-inhibitable Na⫹ inward
current while ASIC1 and ASIC3 are promigratory. ASIC2
expression in the plasma membrane is inversely regulated
by heat shock protein 70 (Hsc70). Thus an increase in
Hsc70, as seen in malignant glioma, leads to a decrease in
the cell surface expression of ASIC2 (194, 609). In a chronic-hypoxia induced pulmonary artery hypertension model,
ASIC1 and ASIC3 keep pulmonary artery smooth muscle
cells in a synthetic migratory phenotype and prevent the
activation of a complex bone morphogenic protein (BMP)
signaling cascade that would drive the differentiation towards a procontractile phenotype (75).
D. Clⴚ Channels
For reasons of electroneutrality, cations crossing the plasma
membrane must be accompanied by anions. Similarly, osmotically relevant salt transport leading to (local) changes
of cell volume requires the simultaneous movement of cations and anions. Thus the evidence for the involvement of
Cl⫺ channels in cell migration is very strong. In fact, research on the role of Cl⫺ channels in glioma cell migration
culminated in first clinical trials (352, 548). Nonetheless,
the number of publications on Cl⫺ channels in cell migration is still relatively low. Part of the delay in Cl⫺ channel
research in the field of migration is most likely due to the
fact that the molecular identity of some Cl⫺ channels such
as the volume-regulated anion channel (VRAC) is still elusive (139).
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SCHWAB ET AL.
Several studies revealed that the migration of fibroblasts
(513), monocytes (280), microglia (659), or nasopharyngeal cancer cells (357, 358) requires VRAC activity. The
expression of the H-ras oncogene in fibroblasts enhances
the volume sensitivity of VRAC leading to faster VRACdependent migration (513). VRAC activity is highly sensitive to changes of the plasma membrane cholesterol concentration. Cholesterol depletion leads to VRAC activation
(286, 324). In this context it is interesting to note that the
plasma membrane cholesterol concentration is twice as high at
the cell front than at the rear part of migrating endothelial cells
(602) that also express VRAC (324). Such asymmetric distribution of cholesterol could sensitize VRAC at the rear part of
migrating cells to changes of cell volume. Thereby, the distinct
chemical composition of the plasma membrane at the front or
rear part of migrating cells could lead to local differences of
VRAC activity at the opposing cell poles and facilitate their
cooperation with KCa3.1 channels that are also more active at
the rear part (520).
1. ClCs, VRAC
The strongest evidence for the involvement of Cl⫺ channls
in cell migration has been obtained for ClC3 and VRAC. In
glioma cells, Cl⫺ is accumulated far above electrochemical
equilibrium (presumably by NKCC1) so that Cl⫺ channel
activity (in conjunction with K⫹ channel activity) elicits
massive Cl⫺ efflux which is accompanied by cell shrinkage
(201). In some migrating tumor cells, Cl⫺ efflux can also be
mediated by KCl cotransporter-4 (KCC4; Ref. 82). Numerous studies show that Cl⫺ channel activity is required for
glioma cell invasion (107, 347, 376, 470, 549, 620) (see
FIGURE 5). A model was put forward according to which
hydrodynamic volume changes mediated by ion channels and
transporters support invasion of glioma cells into and through
the narrow and tortuous extracellular space of brain tissue
(107, 201, 375, 376, 620). ClC3 channels also contribute to
the migration of neutrophils (396, 611), HeLa cells (356),
nasopharyngeal carcinoma cells (355), and wound closure in
Xenopus laevis embryos (163). Possibly, the intracellular
Ca2⫹ concentration plays a coordinating role since ClC3
channels are indirectly regulated by [Ca2⫹]i via their association with calmodulin-dependent protein kinase II (107).
E
2. Other Cl⫺ channels
There are only a few reports on the role of other Cl⫺ channels in cell migration (22, 250, 505, 594), and mechanisms
NPPB
F
-40 mV
3
+40 mV
C
2
1
I (nA)
B
I (nA)
D
4
D
2
A
0
C
B
A
1
0
-1
-1
-2
0
1
2
3
t (min)
4
5
6
-3
-120
-80
-40
0
40
Vm (mV)
FIGURE 5. Involvement of volume-regulated Cl⫺ channels in glioma cell movement. A–D: sequential images
of a migrating D54MG glioma cell. Times indicate when the images were acquired after obtaining a whole cell
patch-clamp recording. The patch pipette is visible as a dark shadow at the lower left hand corner. E: time
course of NPPB-sensitive whole cell current recorded at holding potentials of ⫺40 mV (open symbols) and ⫹40
mV (closed symbols). The current amplitude steadily increased after the cell began to extend a leading process
(white arrow) and contracted its trailing edge. Letters correspond to the images in A-D. Data acquisition was
begun 125 s after establishing a whole cell recording. F: ramp currents from the data in E. Letters correspond
to the time points in E. [From Ransom et al. (470).]
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
of action have not yet been elucidated in detail. Members of
the TMEM16/ANO family are particularly interesting candidates since they are Ca2⫹-sensitive Cl⫺ channels (139,
304) so that their activity could easily be coordinated with
Ca2⫹-sensitive K⫹ channels and/or with other Ca2⫹-dependent mechanisms of cell migration (see sect. IVE). Yet, their
role in cell migration still needs to be further investigated.
So far, this has only been shown for TMEM16A/ANO1
whose overexpression is highly correlated with the occurrence of distant metastases in head and neck squamous cell
carcinoma (HNSCC) (22).
3. GABA receptors
In the developing cerebral cortex, migration of interneurons
and neuroblasts is strongly affected by the function of ionotropic GABAA and GABAC receptors (43, 120, 220). Depending on the expression level of the K⫹/Cl⫺ cotransporter
KCC2 and the resulting shift of the Cl⫺ equilibrium potential, activation of GABAA receptors either leads to a depolarization (low KCC2 expression, high [Cl⫺]i) or to a hyperpolarization (high KCC2 expression, low [Cl⫺]i). A
GABAA receptor-induced depolarization promotes migration of interneurons by activating L-type Ca2⫹ channels
while a GABAA receptor-induced hyperpolarization constitutes a stop signal by abrogating Ca⫹ channel ativation
(43). In oligodendrocyte progenitor cells (NG2 cells),
GABAA receptors cooperate with voltage-activated Na⫹
channels and the Na⫹/Ca2⫹ exchanger NCX1 and promote
migration by inducing a depolarization of the cell membrane potential, too (see sect. IVB) (589). These studies (43,
589) are remarkable for two reasons. On the one hand, they
highlight the importance of the cell membrane potential of
excitable neuronal cells in controlling cell migration. On the
other hand, they illustrate the cell-specific composition of
the GABA receptor-associated transportome that is needed
for efficient cell migration, KCC2 and L-type Ca2⫹ channels
in interneurons, and voltage-gated Na⫹ channels and
NCX1 in oligodendrocyte progenitor cells (NG2 cells).
E. Calcium Regulatory Transport Proteins
Cell migration is a Ca2⫹-dependent process (161, 292, 448,
658) since the migration machinery comprises many Ca2⫹sensitive effector molecules. Examples include myosin II
(34, 37), calpain (155, 346, 600), calcineurin (101, 314),
Ca2⫹/calmodulin-dependent protein kinase (140), gelsolin
(377), integrins, and S100 proteins (575) as well as a number of ion channels and transporters. In addition, Ca2⫹
signaling during migration also induces gene transcription
(591).
The effects of [Ca2⫹]i on the cellular migration machinery
are spatially and temporally regulated with precision. Thus
[Ca2⫹]i is not uniform throughout the cytosol of migrating
cells. It has been known for almost 20 years that there is a
gradient of [Ca2⫹]i along the length axis of migrating cells.
In general, [Ca2⫹]i is higher at the rear part than at the front
of migrating cells (56, 202, 519). This global gradient of
[Ca2⫹]i is at least in part due to the subcellular distribution
of Ca2⫹ storing organelles. The lamellipodium is virtually
organelle-free (3, 102) so that Ca2⫹ release from intracellular Ca2⫹ stores occurs predominantly in the cell body (519).
Recent studies provided a refinement of this view in that
zones of locally elevated [Ca2⫹]i and short-lived “Ca2⫹
flickers” or localized Ca2⫹ transients were revealed at the
leading edge of the lamellipodium of MDCK-F cells and
fibroblasts, respectively (101, 149, 625). These local Ca2⫹
signals that are superimposed on the background of the
global front-rear Ca2⫹ gradient are required for directional
migration by leading to a calcineurin-dependent modulation of cell adhesion. Possibly, Ca2⫹ flickers also regulate
calpain II that is enriched at the front of chemotaxing neutrophils constituting a “frontness” signal promoting polarization (417).
In addition to local and spatially restricted variations of
[Ca2⫹]i and short-lived Ca2⫹ flickers, there is also another
temporal component of [Ca2⫹]i signaling. Transient global
elevations of cytosolic Ca2⫹ are required among others for
migration of neutrophils (226, 353, 359), vascular smooth
muscle cells (503), transformed epithelial cells (519), keratocytes (132), amoebae (345), cortical interneurons (43),
and neuroblasts (292). Similarly, Ca2⫹ transients are involved in regulating nerve growth cone motility (183).
The complexity of Ca2⫹ signaling in cell migration is further increased by its crosstalk with other signaling pathways. Notably, there is a marked crosstalk between Ca2⫹
and cAMP/protein kinase A-dependent signaling (41, 237),
the latter being also an important regulator of cell motility
(378).
Spatial and temporal fine tuning of [Ca2⫹]i contributes to
coordinating the concerted action of different effector proteins. This can be exemplified by considering mechanisms
underlying the retraction of the rear part of a migrating cell
(132, 133, 345). A rise of [Ca2⫹]i triggers contraction of the
actomyosin network following the phosphorylation of the
myosin light chain (644). It induces calcineurin-mediated
release of cell-matrix contacts (314), activates the calciumregulated focal adhesion protein proline-rich tyrosine kinase-2 (Pyk2), as well as the effector proteins paxillin and
p130(Cas) (7). Activation of KCa3.1 and indirectly of ClC3
channels (107) causes a local shrinkage of the rear part of
migrating cells (515). Accordingly, [Ca2⫹]i transients occur
shortly before the retraction of the rear part of migrating
neutrophils or keratinocytes (143, 317). Finally, a rise of
[Ca2⫹]i also triggers the exoytosis of intracellular vesicles
and lysosomes so that silencing members of the synaptotagmin family of calcium-sensing vesicle-fusion proteins such
as SYT7 impair chemotaxis and rear end retraction (100).
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Like in any other cell, the [Ca2⫹]i of migrating cells is determined by Ca2⫹ influx, release and uptake of Ca2⫹ ions
from intracellular stores, and extrusion of Ca2⫹ into the
extracellular space. This is accomplished by a wide variety
of channels, transporters, and pumps located in the plasma
membrane and in the membranes of intracellular Ca2⫹
stores (94). However, despite the importance of [Ca2⫹]i as a
coordinator of different components of the migration machinery, the identification of the spatial and temporal contribution of molecularly defined Ca2⫹ transport proteins to
the mechanisms of cell migration has only begun. This applies in particular to those Ca2⫹ channels, pumps, and exchangers that are responsible for releasing Ca2⫹ from intracellular stores and for removing Ca2⫹ from the cytosol into
intracellular stores or across the plasma membrane into the
extracellular space.
1. TRP channels
A rapidly increasing number of studies has firmly established that transient receptor potential (TRP) channels constitute an important element of the cellular migration machinery. They are especially relevant for migrating cells
since TRP channels are considered as polymodal cell sensors (409). They are activated by many external stimuli,
mediate receptor-operated Ca2⫹ entry, and thereby enable
cells to dynamically adapt their migrational behavior. This
also includes responses to mechanical cues, although the
mechanosensitivity of TRP channels is still a matter of debate (190, 360). Mammalian TRP channels are ubiqui-
A
B
FGF-2
tously expressed, and they are all Ca2⫹ permeable except
for TRPM4 and TRPM5 channels (174).
A) TRPCS. TRPC channels are central constituents of receptor-activated signaling pathways and as such are responsible for the so-called receptor-operated calcium entry
(ROCE) downstream of G protein-coupled receptors. This
mode of activation explains why an increasing number of
studies point to a strong link between TRPC channel function and (chemotactically) directed migration.
I) TRPC1. TRPC1 channels are required for polarization of
migrating cells (149) and/or for their response to external
directional cues in vitro and in vivo (39, 148, 471, 473, 654)
(see FIGURE 6). TRPC1 channel proteins localize to the cell
front of glioma cells chemotactically stimulated with EGF
(39) and of neutrophil granulocytes (281). Consistent with
this subcellular distribution, TRPC1 underlies the local elevation of [Ca2⫹]i at the very cell front of transformed renal epithelial (MDCK-F) cells (149). Thus the impact of TRPC1 channels on local Ca2⫹ dynamics at the cell front and directional
migration appears to be similar to that of TRPM7 channels (see
below; Ref. 625). Importantly, TRPC1 channels primarily control the “steering” mechanism of MDCK-F and glioma cells,
since they have only a minor effect on basal migration. In
glioma and intestinal epithelial cells as well as myoblasts
(346), TRPC1-dependent directional migration is correlated with TRPC1-mediated store-operated Ca2⫹ entry
which in the case of intestinal epithelial cells is enhanced by
forming a complex with STIM1 (39, 473). So far, the mito-
C
FGF-2
FGF-2
180
TRPC1
time (min)
120
50 µm
60
TRPC1
TRPC1
TRPC1
control
20
0
-30
-20
-10
0
10
[µm]
FIGURE 6. TRPC1 channel-dependent chemotaxis of MDCK-F cells in an FGF-2 gradient. A and B: paths of
individual MDCK-F cells migrating in an FGF-2 gradient with the concentration rising towards the right. The
paths are normalized to a common starting point. MDCK-F cells overexpressing TRPC1 channels (A) move up
the FGF-2 gradient while cells with silenced TRPC1 channels (B) do not respond to this chemokine gradient.
C: summary of the chemotaxis experiments shown in A and B. The displacement of the cells into the direction
of the FGF-2 gradient is plotted as a function of time. The open symbols (control) illustrate the random
movement in the absence of an FGF-2 gradient. [Modified from Fabian et al. (148), with kind permission of
Springer Science ⫹ Business Media.]
1882
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20
30
ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
gen-activated protein kinase/ERK1/2 cascade (148, 654),
PI3K/Akt (657), and calpain (346) have been identified as
intracellular signaling pathways and effector proteins involved in TRPC1-dependent migration.
TRPC1 channels are also required for the guidance of nerve
growth cones in response to a number of different neurotropic
factors such as netrin-1, brain-derived neurotrophic factor
(BDNF), or myelin-associated glycoprotein (MAG) (535, 536,
613, 628). TRPC1-dependent axon guidance involves among
other factors intracellular Ca2⫹ signaling via calcineurin and
Slingshot phosphatase (628).
II) TRPC5. Depending on the cell type, TRPC5 channel
activity can have a positive or a negative impact on cell
migration. Possibly, this apparent discrepancy can be accounted for by the magnitude, duration, and localization of
the intracellular Ca2⫹ signal elicited by TRPC5 activation.
Moreover, the presence or absence of TRPC1-TRPC5 heteromers that have a lower Ca2⫹ permeability than monomers can also contribute to the variable effects of TRPC5 on
cell migration (303, 534, 559). In vascular smooth muscle
cells, TRPC5 activation and the resulting (transient) rise of
[Ca2⫹]i triggered by sphingosine-1-phosphate (636) or by
oxidized phospholipids (9) correlates with motility. Similarly, TRPC5 promotes migration of angiotensin II-stimulated podocytes by activating Rac1 in a Ca2⫹-dependent
manner thereby disassembling stress fibers (583). An inverse relation of TRPC5 channels with respect to cell motility is observed in lysophosphatidylcholine (LPC)-stimulated aortic endothelial cells. TRPC5 channels inhibit migration because they trigger a sustained elevation of [Ca2⫹]i
once they have been recruited to the cell membrane in response to an initial TRPC6-mediated increase of [Ca2⫹]i
(78). In hippocampal neurons, TRPC5 channels fulfill a
dual task. They promote axon formation by mediating localized Ca2⫹ influx that activates Ca2⫹/calmodulin kinase
kinase (CaMKK) and its target Ca2⫹/calmodulin kinase I
(111). At the same time, TRPC5-dependent Ca2⫹ transients
limit the linear growth of nerve growth cones presumably
by stabilizing their adhesive contacts (191).
III) TRPC6. TRPC6 channels play an important role in the
migration of endothelial cells and granulocytes. They are
required for VEGF-dependent migration and sprouting in
an in vitro angiogenesis assay of endothelial cells (172,
205). Notably, TRPC6 channels exhibit specificity for
VEGF since FGF-induced tube formation is still present
(172). In human pulmonary arterial endothelial cells, a
mechanism underlying TRPC6 cell surface expression was
identified that has important implications for migration of
other cell types, too. TRPC6 channels interact with the
COOH-terminal tail domain of PTEN (284), which is a
central player in chemotaxis (223). Functional expression
of TRPC6 channels in the plasma membrane and their con-
tribution to angiogenesis requires their interaction with
PTEN (284).
Endothelial cells play an important role in recruiting granulocytes from the bloodstream to sites of infection or inflammation with selectin-mediated interactions between endothelial cells and leukocytes being one of the earliest steps
in this cascade. TRPC6 channels that are expressed in granulocytes (109, 379, 531) are involved in this process. This
was assessed in a model of an allergic airway response
(531). Less eosinophil granulocytes, IL-5, and IL-13 are
isolated from bronchoalveolar lavage fluid from TRPC6⫺/⫺
compared with that from wild-type (wt) mice. These observations can be explained in two ways. Either lower cytokine
secretion leads to a decreased maturation and weaker stimulation of eosinophils, or the infiltration/migration process
itself is impaired. The following observations lend support
to the second possibility. In neutrophils, TRPC6-dependent
Ca2⫹ signaling induced by soluble E-selectin is augmented
by the simultaneous application of the chemoattractant
platelet activating factor (PAF) (379). Moreover, TRPC6⫺/⫺
neutrophils cover shorter distances on a two-dimensional
glass surface than wt cells when stimulated with macrophage inflammatory protein-2 (MIP-2) (109). Finally, unpublished findings from our laboratory revealed a severe
chemotaxis defect of neutrophils from TRPC6⫺/⫺ mice.
Thus TRPC6 channels appear to function as central players
in granulocyte recruitment by integrating selectin and chemoattractant receptor signaling.
Besides their role in cell proliferation and cell cycle progression (60, 579), TRPC6 channels also promote tumor cell
invasiveness. In glioblastoma, hypoxia-induced upregulation of TRPC6 channel expression, depending on Notch
signaling, importantly contributes to an aggressive phenotype with increased invasiveness by activating the the calcineurin/NFAT pathway in a Ca2⫹-dependent way (90).
B) TRPVS.
TRPV5 and -6 are the TRP channels with the
highest Ca2⫹ selectivity. However, to the best of our knowledge, there are no studies directly investigating their role in
cell migration. Nonetheless, such a role is conceivable given
the fact that TRPV6 channels are partners of KCa3.1 channels in prostate cancer cells (306).
I) TRPV1. A series of papers characterized the interplay
between TRPV1 channels and microtubules in regulating
the movement of nerve growth cones of dorsal root ganglial
(DRG) cells or of TRPV1 transfected neuroblastoma ⫻
DRG neuron hybrid cells (184 –186, 188). The COOHterminal part of TRPV1 interacts with microtubules and
thereby stabilizes them while the activation of TRPV1 channels promotes the disassembly of dynamic microtubules
that can account for the shortening of DRG neurites following TRPV1 activation. At least part of the effects of TRPV1
channels on the microtubule network can be classified as a
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SCHWAB ET AL.
“nonconductive property” that is mediated by intracellularly localized NH2- and COOH-terminal domains of the
channel (186). In hepatocyte growth factor (HGF)-stimulated HepG2 hepatoblastoma cells, activation of TRPV1
channels enhances migratory activity. Due to a differential
effect of TRPV1 on stable and dynamic microtubules (185),
it was speculated that activation of TRPV1 with capsaicin
could have modulated microtubule dynamics at the rear
part of the cells in a way that allows an easier retraction of
this cell pole, thereby stimulating migration (617). In corneal epithelial cells, TRPV1 stimulates migration by transactivating the EGF receptor (643).
II) TRPV2. TRPV2 channels contribute to the migration
and chemotaxis of macrophages (337, 403) and PC3 prostate cancer cells (393). In a murine macrophage cell line
(TtT/M87) and PC3 cells, TRPV2 channels are translocated
from the endoplasmic reticulum to the plasma membrane
following stimlation with fMLP and LPC or lysophosphatidylinositol, respectively, which then underlies the sustained
agonist-induced Ca2⫹ influx and chemotaxis. Importantly,
TRPV2 expression is higher in samples from patients with
metastatic disease than in solid primary tumors consistent
with its role in tumor cell migration (394).
III) TRPV4. Mechanosensitive Ca2⫹ channels play an important role in coordinating the movement of the front and
rear part of migrating cells and in the response to an altered
mechanical load of cell-matrix contacts (317). However, so
far the molecular nature of mechanosensitive Ca2⫹-permeable channels in migrating cells is still elusive. TRPV4 channels contribute to cell volume regulation (28, 30) and other
mechanical responses such as ciliary beating under viscous
strain (12) or mechanical hyperalgesia (10). Applying external forces to focal adhesion complexes via the movement of
magnetic beads leads to an almost instantaneous activation
of TRPV4 channels and Ca2⫹ influx into the stimulated
endothelial cells (369). Such findings make TRPV4 channels an attractive candidate for the elusive mechanosensitive Ca2⫹ channel in cell migration. This view is further
supported by observations that TRPV4 channels indeed affect cell migration. Stimulation of TRPV4 channels with
their activator 4␣-PDD increased lamellipodial dynamics
of HepG2 hepatoblastoma cells (617). They are required
for the realignment of endothelial cells under cyclic strain
(580), and TRPV4 channels mediate arachidonic acidinduced migration of breast cancer-derived endothelial
cells that express these channels at a much higher level
than “normal” endothelial cells (152). On the other
hand, a careful analysis of their role in migration of an
immortalized neuroendocrine cell line (GN11) came to
the opposite conclusion providing further evidence for
the importance of the cellular context (transportome) of
a given ion channel for cell migration and the temporal
pattern of its activation.
1884
C) TRPMS.
TRPM channels were first dicovered as a tumor
suppressor in melanoma (TRPM1), and expression of other
TRPM channels has been linked with tumors (297). However, recent studies show that they are also involved in
controlling immune cell function and motility of a number
of other cell types. Some of its members, TRPM2, -6 and -7,
are “chanzymes” combining the function of an ion channel
and an enzyme in the same protein (174) so that their impact on cell migration is at least partially due to their nonconductive properties.
I) TRPM2. TRPM2 channels play an important role in
neutrophil recruitment. They are involved in increasing the
endothelial permeability in oxidant-stressed tissue (221),
and they are required for chemotaxis of neutrophils towards fMLP (365, 442) and for chemokine production by
macrophages (640). In neutrophil granulocytes, TRPM2
channels are activated by ADP-ribose that is formed intracellularly following stimulation with chemoattractants such
as fMLP (222). Interestingly, TRPM2⫺/⫺ neutrophils behave normally in a gradient of another chemokine, CXCL2
(640). Nonetheless, neutrophils do not infiltrate the colonic
mucosa in a colitis model in TRPM2⫺/⫺ mice, which involves elevated CXCL2 expression. In this model, TRPM2
channels support neutrophil chemotaxis rather indirectly
since they are required for chemokine production by macrophages (640). The link between TRPM2 channels, inflammation, and chemokine production is given by reactive
oxygen species (ROS) that are released by neutrophils and
are potent activators of TRPM2 channels (215).
It is intriguing to note that distinct TRP channels in neutrophils appear to be coupled to distinct signaling pathways
and thereby mediate the migratory response of neutrophils
to different chemoattractants. TRPM2 channels are linked
to the fMLP receptor, while TRPC6 channels appear to
couple to the CXCR2 receptor (109). It is tempting to speculate that spatially restricted Ca2⫹ signals locally trigger the
signaling cascades downstream of the respective receptors.
Such local regulation could also involve intracellularly localized TRPM2 channels as evidenced in dendritic cells. In
these cells, efficient chemotaxis requires TRPM2-mediated
Ca2⫹ release from lysosomes (565).
II) TRPM4. TRPM4 is a Ca2⫹-activated channel permeable
only for monovalent cations that controls the [Ca2⫹]i indirectly by setting the cell membrane potential (see sect. IIIA).
So far, the role of TRPM4 channels in cell motility has been
studied only in immune cells. In TRPM4⫺/⫺ mice, migration of dendritic cells to lymphoid organs is impaired because chemotaxis is inhibited due to a Ca2⫹ overload-dependent downregulation of PLC-␤2. When dendritic cells
are matured with fixed Escherichia coli, the defect in chemotaxis overrides the increased migratory activity that has
almost doubled in TRPM4⫺/⫺ dendritic cells (23). A similar
phenotype was observed in bone marrow-derived mast cells
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
A
B
C
Trpm4-/-
Trpm4+/+
Trpm4+/+
Trpm4-/-
**
100 µm
100 µm
chemotaxis index
4
2
0
0
25
0
25
CCL 21 (ng/ml)
FIGURE 7. Migration and chemotaxis of dendritic cells depends on TRPM4 expression. A and B: trajectories
of individual dendritic cells from wild-type (A) and TRPM4⫺/⫺ (B) mice. The longer cell paths reveal that TRPM4
deficiency leads to increased migratory activity of dendritic cells that are stimulated with fixed E. coli.
C: summary of chemotaxis experiments. Although wild-type dendritic cells migrate more slowly than
TRPM4⫺/⫺ cells, their chemotaxis towards CCL21 is more efficient. [From Barbet et al. (23), with permission
from Nature Publishing Group.]
family of ␣-kinases that is a relative of the Dictyostelium
myosin heavy chain kinase that can induce myosin II filament disassembly (97). Thus TRPM7 is a prototype channel
with pronounced nonconductive properties. Earlier studies
focused on the impact of TRPM7 channels on cell adhesion
(96, 562). Several other recent studies addressed the role of
TRPM7 channels in cell migration (1, 61, 79, 169, 339,
496, 563). In migrating fibroblasts TRPM7 produces shortlived local increases of [Ca2⫹]i (“Ca2⫹ flickers”) at the leading edge (see FIGURE 8) (625). Their accentuation by mechanical stimulation is consistent with earlier studies on the
cellular localization of mechanosensitive Ca2⫹ influx at the
cell front (399) and with the reported mechanosensitivity of
TRMP7 channels (415). Thus TRPM7 is another candidate
stimulated with stem cell factor (SCF) (538). These studies
represent further examples for the dissociation of ion channels’ impact on the “migratory motor” and the “steering
wheel” of a migrating cell (see FIGURE 7). The impact of
TRPM4 channels on cell motility critically depends on the
expression level. Th2 cells express more TRPM4 channels
than Th1 cells. Blocking TRPM4 channel function results in
amplified intracellular Ca2⫹ signals in Th2 cells while they
are reduced in Th1 cells. Conversely, migratory activity is
impaired in Th2 cells, while it is increased in Th1 cells
following TRPM4 inhibition (624).
III) TRPM7. TRPM7 is a Ca2⫹- and Mg2⫹-permeable ion
channel with a kinase domain (493, 494) that belongs to the
A
B
RGDS 2 mM, 1 min
(-) Blebbistatin 100 µM, 10 min
N
20 µm
Cytochalasin D 2 µM, 5 min
80 µm
5s
80 µm
FIGURE 8. TRPM7-mediated calcium flickers. A: overlay of calcium flicker ignition sites (red dots) and focal
adhesions (green; integrin ␣5 staining). Enlarged views of calcium flickers, focal adhesions, and their overlay
are shown to the right (top, middle, and bottom, respectively). N denotes the nucleus. B: calcium flickers in the
lamellipodium before (left) and after (right) modifying traction force by applying an integrin ligand (RGDS
peptide), blebbistatin, or cytochalasin. These treatments predominantly affect the flicker probability rather than
its amplitude. [From Wei et al. (625), with permission from Nature Publishing Group.]
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1885
SCHWAB ET AL.
channel for the elusive mechanosensitive Ca2⫹ channel of
migrating cells. The frequency of TRPM7-mediated Ca2⫹
flickers also correlates with the cells’ turning behavior in
chemotactic gradients of PDGF (625). Moreover, in an in
vitro wound healing assay with Swiss 3T3 fibroblasts (563)
and during Xenopus laevis gastrulation (339), TRPM7
channels drive the polarization of migrating cells. Thus
Ca2⫹ signals at the leading edge appear to be part of a local
feedback system underlying cell polarity (99, 147). In line
with the concept of a cell-specific transportome, the role of
TRPM7 channels in directional persistence or polarization
can be taken over by TRPC1 channels (149).
tion with TRPC1 to promote wound healing in a “scratch
assay” of epithelial restitution (473). In vascular smooth
muscle cells isolated from rat aorta, PDGF-induced Ca2⫹
entry and the resultant stimulation of migration depend on
Orai1/STIM1. This is pathophysiologically relevant since
the expression of Orai1/STIM1 is upregulated in ballooninjured carotid arteries (35). Mechanical injuries of the vascular wall lead to enhanced migration of the vascular
smooth muscle cells. Orai1 expressed in endothelial cells
contributes to VEGF-induced chemotaxis and angiogenesis
(327).
2. P2X receptors
The story about TRPM7 and cell polarization took a new
twist by revealing that Ca2⫹ can be substituted and/or supported by local Mg2⫹ influx (496). Thus the defect in cell
polarization and in gastrulation following TRPM7 knockdown is rescued by expressing the Mg2⫹ transporter
SLC41A2 (339, 563), and preventing Mg2⫹ influx by
TRPM7 silencing impairs the migration of osteoblasts (1).
Orai and STIM proteins mediate Ca2⫹ release
activated Ca2⫹ (CRAC) current with Orai proteins constituting the conductive pathway for Ca2⫹ and STIM being
the sensor of the filling status of the ER Ca2⫹ stores (58).
Since they are closely linked to TRP channel function, we
will discuss these proteins here. Reflecting the eminent importance of CRAC current following receptor stimulation,
several recent studies addressed the role of Orai/STIM in
chemotactically or chemokinetically stimulated migration
with a particular focus on cell adhesion. Current evidence
indicates that integrin outside-in signaling is a common target of Orai1/STIM1-mediated Ca2⫹ signaling in cell migration. Orai1 plays a role in the recruitment of neutrophils
from the blood flow to the endothelium (130, 501). Reduced Orai1 expression delays the onset of arrest and polarization of neutrophils on the endothelium under shear
flow conditions because the accompanying intracellular
Ca2⫹ signal is attenuated (501). Orai1-mediated Ca2⫹
influx is triggered by engagement of high-affinity LFA-1
whose clustering as well as actin polymerization at the cell
front are promoted by colocalized Orai1 (130). The activation status of LFA-1 appears to play a decisive role in its
interaction with Orai1, since the migration of T lymphocytes without shear stress is independent of Orai1 (567).
STIM1-deficient T cells lack store-operated Ca2⫹ entry
(SOCE) in response to CXCL11, CCL19, and CCL20 via
stimulation of CXCR3, CCR7, and CCR6 receptors,
respectively, leading to impaired chemotaxis. This defect
contributes to the protection from experimental allergic encephalomyelitis (EAE) in T cell-specific STIM1-deficient
mice (349). Orai1 and STIM1 are also involved in the migration of serum-stimulated breast (645) and EGF-stimulated cervical cancer cells (81). In both cancers, altered
STIM1 expression indicates poor patient prognosis (81,
372). In intestinal epithelial cells, STIM1 acts in conjuncD) ORAI/STIM.
1886
In addition to the purinergic P2Y receptors (301), some
members of the P2X family of ATP-gated ion channels
(P2X1, P2X4, and P2X7) have been implicated in cell migration and chemotaxis, especially in immune cells (316, 421).
ATP itself, however, is not a chemoattractant but rather
acts as an autocrine amplifier for other chemoattractants
such as C5a (249). P2X1, P2X4, and P2X7 are commonly
found in cells of the immune system (117, 209, 619). At first
sight, P2X7 receptors are least likely to be involved in cell
migration, since channel activation requires greater than
⬃300 ␮M ATP, well beyond saturating concentrations
(⬃100 ␮M ATP) for the other P2X family members (412).
However, P2X7 receptors are highly expressed in some cancers including breast and thyroid cancer (545, 547). In
breast cancer cells, P2X7 together with KCa2.3 contributes
to cystein cathepsin-dependent tumor cell invasiveness
(259). The proinvasive effect of P2X7 receptors depends on
the activity of KCa2.3 channels, which are probably activated by the P2X7-mediated rise of the intracellular Ca2⫹
concentration.
Pharmacological inhibition or siRNA knockdown of P2X4
receptors decreases ATP-induced chemotaxis (421) and
morphine-induced migration of microglial cells (235) by as
yet undefined mechanisms. P2X4 or other P2X receptor
subtypes could contribute to Ca2⫹ flickers at the leading
edge (625). Alternatively, P2X4-mediated cation influx
could lead to osmotic water uptake and local swelling, if it
occurred predominantly at the cell front. P2X1 receptordeficient neutrophils migrate more slowly than wild-type
cells, and the authors deduced that P2X1 activation leads to
increased Rho activity and trailing end retraction by an
unknown mechanism (316).
3. Na⫹/Ca2⫹ exchanger
The temporal and spatial “shape” of intracellular Ca2⫹
signals critically depends on transport proteins mediating
the export of Ca2⫹ across the plasma membrane or into
intracellular stores. Their role in cell migration is presently
underestimated. One of the relevant transport proteins in
this context is the NCX (348). Depending on the electro-
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
chemical gradients, however, the Na⫹/Ca2⫹ exchanger can
export (forward mode) or import Ca2⫹ (reverse mode).
NCX is inhibited by the isothiourea derivative KB-R7943,
which is ⬎10-fold more potent in inhibiting the reverse than
the forward mode (253). We showed that in migrating
MDCK-F cells the Na⫹/Ca2⫹ exchanger is one of the major
components of the Ca2⫹ efflux machinery required for cell
migration (134). Moreover, we observed that (forward)
NCX activity is also necessary for PAF-stimulated migration of human neutrophil granulocytes (unpublished observation from our laboratory). NCX also participates in the
migration of oligodendrocyte progenitor (NG2) cells (589),
primary cardiac myofibroblasts (466), tendon fibroblasts
(499), microglia (244), pancreatic cancer (131), and corneal
endothelial cells (89). In these cell types, Na⫹/Ca2⫹ exchange was reported to be operating in the reverse mode.
However, reverse mode of operation was not shown in all
cells. In microglia or in cardiac myofibroblasts, it was inferred from the use of KB-R7943 (244, 466). Some caution
is justified at this point since the KB-R7943 sensitivity
strongly depends on the NCX1 splice variant. The cardiac
splice variant, NCX1.1, is relatively insensitive to KBR7943 when operating in the forward mode (IC50 ⬎30
␮M) (253), while splice variants NCX1.3 and NCX1.7 are
inhibited in their forward mode by KB-R7943 with IC50
values of 2–3 ␮M (206). To the best of our knowledge, it is
not yet known which NCX isoforms are expressed in primary cardiac myofibroblasts or microglial cells.
or K⫹-Cl⫺ cotransport (659)] or actin polymerization (428)
leads to local water flow supporting the formation of protrusions (435). Accordingly, lamellipodial activity is enhanced upon expression of aquaporins (497). A theoretical
analysis comes to a similar result, namely, that an osmotic
gradient elicits water fluxes that result in the movement of
cells (256). Water flow into the lamellipodium would also
be in line with the so-called Brownian ratchet model. This
model predicts that bending of actin filaments due to thermal fluctuations makes room for actin monomers to polymerize with their barbed ends pointing towards the plasma
membrane at the leading edge. When the elongated actin
filaments recoil, they exert an elastic pushing force on the
membrane and thereby protrude the leading edge of the
lamellipodium (390). As a consequence of local water influx, intracellular constituents such as actin monomers are
diluted. The resulting concentration gradient may drive actin polymerization in growing filopodia by steepening the
gradient from the cell body into the filopodium and thereby
promote forward flux of actin monomers (343). Water flow
across the plasma membrane of the leading edge also provides an additional protrusive force because the poroelastic
nature of the cytoplasm (386) prevents the immediate dissipation of a localized volume increase at the front. In addition to their transport-related effects on cell migration,
aquaporins also elicit other effects based on their impact on
the [Ca2⫹]i (294) or nonconductively by interacting with
other intacellular proteins such as Lin-7/␤-catenin (395) or
PKC-␰ and Cdc42 (343).
F. Aquaporins
The contribution of aquaporins to the cellular migration
machinery has important pathophysiological implications
and therapeutic potential in oncology (435). AQP1 contributes to tumor angiogenesis (497) and drives metastases by
promoting tumor cell extravasation (238). Its (over)expression in breast cancer cells (430) like that of AQP5 in chronic
myeloid leukemia cells (73) and non-small-cell lung cancer
(NSCLC) (350) correlates with poor prognosis. Moreover,
aquaporins are important modulators of the wound healing
process. AQP1 and AQP3 are required for efficient restitution of the wounded corneal epithelium (322, 492). Similarly, AQP3 is involved in wound healing of the skin (63,
214). The beneficial effects of EGF on wound closure are
closely correlated with EGF-induced AQP3 expression
(63). On the other hand, genetic deletion of AQP4 greatly
reduces glial scar formation (21, 498). Finally, the role of
aquaporins in the migration of immune cells qualifies them
as potential targets in the treatment of inflammatory diseases (212, 270, 328, 342).
The discovery that aquaporins constitute important components of the cellular migration machinery was a major
breakthrough in the field (see FIGURE 9; reviewed in Refs.
128, 344, 435). It provided strong support for the model
that ion channels and transporters involved in cell migration can do so by inducing local changes of cell volume.
Regardless of the cell type, genetic deletion of aquaporins in
mice or knockdown of aquaporins in cultured cells is accompanied by reduced migratory activity. The involvement
of aquaporins 1, 3, 4, 5, 7, and 9 in cell migration was
shown in in vivo and in vitro in endothelial (242, 395, 497),
melanoma (238), glial (374, 498), renal proximal tubular
(213), corneal epithelial (322), gastric epithelial (218) and
gastric carcinoma cells (241), chondrocytes (331), keratocytes (214, 492), neutrophils (270, 342), dendritic cells
(212), fibroblasts (63), lung adenocarcinoma (83), and neuronal stem cells (294). The widespread “use” of multiple
aquaporins in cell migration clearly points to the universal
nature of this mechanism. Several studies have shown that
aquaporins are concentrated at the leading edge of the lamellipodium (213, 342, 497, 498) and that water flux is
increased in motile cell regions of neutrophils (342). It was
proposed that a local osmotic disequilibrium at the cell
front induced by local ion fluxes [e.g., by Na⫹/H⫹ and
Cl⫺/HCO3⫺ exchange (287), Na⫹-K⫹-2Cl⫺ (200, 404, 527)
V. TRANSPORTERS INVOLVED
IN CELL MIGRATION
TABLE 2 gives a synopsis of this section, listing all transport-
ers and their function in cell migration that will be discussed
in detail in the following part.
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1887
SCHWAB ET AL.
A
160
Number of blood vessels
per mm2
100
Survival (%)
120
AQP1-/50
AQP1+/+
0
0
20
40
80
***
40
**
0
140
+/+ -/<10
Time (days)
+/+ -/10-20
+/+ -/>20
Vessels diameter (µm)
B
AQP1+/+
Speed of wound edge (µm · h-1)
0
1
2
3
4
5
+/+
AQP1-/-
200 µm
-/-
**
24 h
0h
C
Control
AQP1
Control
AQP1
Number of ruffles
per cell
0
1
2
3
Control
AQP1
50 µm
*
20 µm
FIGURE 9. Involvement of aquaporins in cell migration. A: AQP1⫺/⫺ mice have an extended survival with
subcutaneous melanoma (left). This beneficial effect of AQP1 knockout is due to impaired angiogenesis. The
number of vessels in subcutaneous melanoma is lower in AQP1⫺/⫺ than in wild-type mice (right). In vitro
analysis shows that (B) wound healing of cultured endothelial cells occurs more slowly in cells from AQP1⫺/⫺
than from wild-type mice (left; blue, initial wound edge; red, after 24 h) which is quantified as the wound edge
speed (right). C: transfecting CHO cells with AQP1 enhances their migratory activity which is illustrated by
longer paths of individually tracked cells (left). Cells were tracked over 4 h, and arrows indicate initial positions.
Middle and right: AQP1 expression increases the number of ruffles at the leading edge of the lamellipodium,
which correlates well with the increased protrusive activity. [From Saadoun et al. (497), with permission from
Nature Publishing Group.]
A. pH Regulatory Transport Proteins
Intra- and extracellular pH homeostasis reflects the integrated function of intra- and extracellular buffers, pH-regulatory transport proteins, and the production/consumption of protons by metabolism (42). Precise pH regulation
by transport proteins that move acids or bases across the
plasma membrane is mandatory for all cells (488), since the
protonation of proteins is a crucial determinant of their
function. Accordingly, the function of proteins comprising
the cellular migration apparatus is also pH dependent. That
cell migration is a pH-dependent process was discovered
already in the 1920s (233). Since then, many studies have
1888
shown that intra- and extracellular pH (pHi and pHe) are
critical determinants for efficient cell migration (57, 118,
217, 287, 299, 351, 436, 476, 481, 552, 554, 556). The
interrelation of pH and cell migration is of particular pathophysiological importance in tumor metastasis and innate
immune cell function.
In solid tumors, hypoxia insufficient vascularization and
tumor anemia with a reduced oxygen transport capacity of
the blood lead to a switch to glycolytic metabolism resulting
in an extensive production of lactate and protons (225, 300,
465). pHi is defended and may even become more alkaline
than in normal cells (177) by increasing acid export so that
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
Table 2. Transporters involved in cell migration
Transporter
Cell Type
Function in Cell Migration
Reference Nos.
Na⫹/H⫹ exchanger
NHE1
MDCK-F cells
Moloney Sarcoma virus transformed MDCK
cells
melanoma cells
neutrophils
fibroblasts
Dictyostelium discoideum
breast carcinoma cells
cervix carcinoma cells
gastric myofibroblasts
human umbilical vein endothelial cells
NHE2
PC12 cells, neocortical neurons
mouse gastric epithelial cells
supports migration by mediating solute uptake at the
cell front;
involved in directionality of migration
blockade inhibits migration by altering actin
cytoskeletal dynamics
blockade inhibits migration; generates pH gradients
extracellularly (within glycocalyx) and intracellularly
to locally regulate ␤1-integrin mediated cell
adhesion and cytoskeletal dynamics
promotes migration by mediating cell swelling;
permissive role in migration by maintaining pHi
homeostasis
links actin cytoskeleton to the plasma membrane via
linkage with ERM proteins;
regulates cell polarization and directionality of
migration;
positive feedback loop between Cdc42 and NHE1
necessary for cell polarity;
activates cofilin by intra-invadopodial alkalinization;
directional migration in response to ciliary PDGFR-␣
signals depends on NHE1
knock-out impairs polarization and chemotaxis by
loss of cofilin-dependent actin dynamics
promotes invasion and invadopodial ECM proteolysis
through acidification of the peri-invadopodial
space;
upregulated by EGF, contributes to basal and
EGF-stimulated migration
blockade inhibites IGF-stimulated migration
knockdown inhibits HIF-1␣ induced migration and
tube formation by reducing calcpain-2 expression
promotes nerve growth cone outgrowth
required for trefoil factor 2-induced repair
287
126, 524
305
299, 361, 554,
556, 561
481, 490, 631;
217
119
118
157
351
514
92, 443
57, 64, 65,
437, 476
86
108
388
543
638
⫺
Na⫹/HCO3
cotransporter
MDCK-F cells
supports migration in short but not long time scales
524
Monocarboxylate transporter (MCT)
MCT1
endothelial cells
MCT4
MDA-MB-231 breast cancer cells
retinal pigment epithelial cells
mediates lactate uptake, triggers an autocrine
NF-␬B/IL-8 pathway driving migration and tube
formation
knockdown impairs migration
colocalizes with ␤1-integrins at the leading edge
605
168
167
Na⫹/K⫹/2Cl⫺ cotransporter
NKCC1
tadpole keratocytes
MDCK-F cells
glioma cells
PC12D cells
inhibition impairs migration
inhibition impairs migration
inhibition impairs in vivo tumor invasion
promotes neurite outgrowth
32
527
200
404
Na⫹/Ca2⫹ exchanger
NCX1
cardiac ventricular myofibroblast
NG2 cells
tendon fibroblasts
inhibition impairs PDGF-BB-induced motility
activity in reverse mode supports migration
inhibition and siRNA impairs migration
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466
589
499
1889
SCHWAB ET AL.
Table 2.—Continued
Transporter
Cell Type
microglia
MDCK-F cells
pancreatic cancer cells
Function in Cell Migration
blockade inhibits bradykinin-induced migration
forward mode operation required for migration
reverse mode imports Ca2⫹ required for TGF-␤
stimulated migration
Reference Nos.
244
134
131
Na⫹-K⫹-ATPase
␣-subunit
␤-subunit
FXYD
tadpole keratocytes
glioblastoma cells
cytotrophoblast cells
Moloney sarcoma transformed MDCK cells
cerebellar granule cells
glioma cells
pancreatic cancer cells
airway epithelial cells
ouabain inhibits migration
UNBS1450 inhibits migration
marinobufagenin inhibits chemotaxis/invasion
downregulation increases motility via Rac1 and PI3K
antibodies against AMOG/␤2 inhibit migration
AMOG/␤2 increases adhesion and decreases
migration
FXYD5 increases motility and metastatic potential
FXYD5 increases motility
the extracellular compartment is acidified (87, 569). Thus,
in solid tumor tissues, pHe reaches values of pHe 6.5 and
lower (603). This characteristic metabolic tumor microenvironment in turn increases the metastatic potential (67,
179, 622). The acidic and lactate-enriched tumor microenvironement can also provide an explanation for the inability
of the immune system to eliminate tumor cells. Lactate stimulates the migration of tumor cells, while it inhibits migration of monocytes (180) and impairs the differentiation of
tumor-associated dendritic cells (189). Conversely, increasing pHe in tumors by oral NaHCO3 reduced the formation
of spontaneous metastases in mouse models of metastatic
breast cancer (483). Since tumor cell migration constitutes
one of the hallmarks of cancer and is one of the prerequisites for tumor metastasis (207, 208), the underlying pHiand pHe-dependent mechanisms offer therapeutic potential.
Similarly, it is well established that inflamed tissues are
characterized by an acidic and hypoxic microenvironment.
This applies to inflammatory reactions against exogenous
pathogens (542) and to autoimmune processes such as
rheumatoid arthritis (618). Local hypoxia and acidosis of
the inflamed tissue are at least in part due to the massive
recruitment of immune cells with high metabolic activity
(291). It has profound effects on cells of the innate immune
system (104, 363). Like in tumors (164, 635), the acidic and
hypoxic microenvironment can impact directly on the cellular migration machinery or elicit indirect effects by altering the secretion of chemokines (44, 364). The hypoxic
microenvironment also leads to the upregulation HIF-1␣
(660). Notably, HIF-1␣ in turn regulates the expression of
the Na⫹/H⫹ exchanger NHE1, which is one of the major
pH-regulating transport proteins involved in the migration
of neutrophils and tumor cells (539).
1890
32
320
597
24, 468
14
532
537
385
pHe and pHi have multiple effects on the cellular migration
machinery. As already outlined in section IIB, integrin-mediated cell adhesion is pH dependent (321, 436, 554). Studies from our laboratory revealed that it is rather the pericellular pHe within the glycocalyx than the global extracellular
pH of the bulk solution surrounding migrating cells that
controls adhesion and migration (556, 561). Integrins protude by ⬃20 nm above the surface of the plasma membrane
(145, 574) so that the interaction of integrins with extracellular matrix proteins takes place within the pericellular nanoenvironment. We could show that the pericellular proton
concentration within the glycocalyx is up to twice as high at
the leading edge than at the rear part of migrating melanoma cells (299, 556). Molecular dynamics simulations and
force measurements with atomic force microscopy indicated that pHe has a strong impact on the conformation of
integrins (see FIGURE 10). An acidic pHe facilitates the activation of ␣v␤3 integrins (436). Thus the gradient of the
pericellular proton concentration causes integrins to be in a
more activated state at the cell front than at the rear end of
migrating cells. This facilitates the formation/stabilization
of focal adhesion contacts at the cell front and their release
at the rear part, respectively. Moreover, the proton-dependent activation of integrins can account for the increased
adhesion of melanoma cells to a collagen matrix in an acid
environment (554).
The extracellular pH gradient within the pericellular space
is accompanied by a complementary intracellular pH gradient in melanoma and other cell types such as endothelial
cells or in nerve growth cones. pHi is more alkaline at the
cell front than at the rear part (361, 487, 543)(see below for
a more detailed discussion). The alkaline pHi at the cell
front (relative to pHi at the rear part) will lead to a higher
focal adhesion turnover at the cell front due to the lower
Physiol Rev • VOL 92 • OCTOBER 2012 • www.prv.org
ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
units higher at the leading edge (283). This pHi gradient is
of the same order of magnitude as in migrating melanoma
cells (361).
In
ac sid
tiv eat ou
io t
n
H+
H+
FIGURE 10. Model of pH-regulated integrin activation. Following
inside-out activation, acidic extracellular pH can promote integrin
headpiece opening from the extended-closed to the extended-open
conformation. In addition, acidic pH can stimulate headpiece opening on the bent-closed integrin. Thus there are two ways by which
acidic extracellular pH can cause integrin activation. Based on the
extracellular pH gradient at the cell surface (556, 561), the protondependent activation of integrins causes cell adhesion to be stronger at the cell front than at the rear part of migrating cells. [From
Paradise et al. (436).]
affinity of talin for binding actin and decreased maximal
binding at higher pHi (551). Complementary local pH nanoenvironements are also found in invadopodia. Pericellular and intracellular pH of invadopodia are more acidic and
alkaline than in neighboring regions, respectively (57, 351).
Thus we have a spatial organization of the intracellular
proton concentration that is reminiscent of the spatial distribution of the intracellular Ca2⫹ concentration (625): a
global front-rear gradient and local subdomains.
In addition to cell adhesion, pHi affects actin polymerization by regulating the actin-severing protein cofilin whose
activity increases with rising pHi (33, 454). The underlying
mechanism is a pH-dependent disinhibition of cofilin by a
decrease of cortactin binding (351). By severing actin filaments, activated cofilin thereby generates new sites for actin
filament assembly at the cell front or in invadopodia (351,
361, 487). Cofilin is inhibited by PI(4,5)P2 binding which in
itself is pH dependent. PI(4,5)P2 binding to cofilin is lower
at pH 7.5 than at pH 6.5 so that pH-dependent binding of
PI(4,5)P2 constitutes a second mechanism to account for the
pH sensitivity of cofilin (156, 550). The intracellular alkalinization required for cofilin activation is brought about by
NHE1 that is stimulated by many migrational cues such as
growth factors (514). Similar pH-driven dynamics of a cytoskeletal motor of migration is found in ameboid sperm of
the nematode Ascaris suum. Ameboid locomotion of these
cells is based on treadmilling of the socalled major sperm
protein (MSP) with polymerization at the cell front and
depolymerization at the rear. Ascaris suum sperm establishes a pseudopodial pH gradient, with pHi being 0.15 pH
pHi also regulates mechanisms underlying the retraction of
the rear end of a migrating cell (103, 607) by interfering
with Ca2⫹-dependent signals. While Ca2⫹ binding to calmodulin does not change when pHi is decreased from pH
6.8 to pH 7.2 (420), the interaction of calmodulin with its
effectors such as calcineurin and myosin light-chain kinase
is pH sensitive. An acidification increases their Ca2⫹ sensitivity, thereby allowing enzyme activation in the presence of
suboptimal Ca2⫹ (240). Thus the intracellular pH gradient
(361, 487) acts synergistically with the intracellular Ca2⫹
gradient in activating myosin light-chain kinase and consequently myosin II at the rear part of migrating cells.
Most cells migrate through a three-dimensional network of
extracellular matrix proteins. Depending on the cell type,
proteolytic digestion of the extracellular matrix is an essential step for efficient migration or invasion. This is particularly relevant for tumor cells (67, 278). The acidic tumor
microenvironment and the local nanoenvironment surrounding invadopodia (57), which is generated by the activity of pH regulatory (transport) proteins, facilitates the
action of proteases that are mostly secreted by stromal cells.
Proteases either have their pH-optimum in the acidic range
[e.g., MMP-3 (231), urokinase-type plasminogen activator
(281), cathepsin D (333, 577), cathepsin B (572), and cathepsin L (391)], depend on the protonation of their substrate [e.g., MMP-2 (392)], or their conversion from inactive pro-MMPs to active MMPs is promoted by an acidic
microenvironment (288). In addition, release and expression of proteases are also upregulated by a low pHe (45,
272, 391). The latter process requires Ca2⫹ influx that is
inhibited by blockers of voltage-gated Ca2⫹ channels (273).
Taken together, these studies clearly indicate that an acidic
extracellular pH can activate a whole toolkit of proteases,
thereby facilitating invasion and migration through the extacellular matrix.
Finally, many of the transport proteins involved in cell migration are pH sensitive themselves. Modulation occurs in
both directions. KCa3.1 channels, for example, are inhibited
by an intracellular acidosis (445), while channels like
TRPV1 or ASICs are activated by extracellular protons
(232). Yet other channels like TRPM7 respond to an
extracellular acidification in a more complex way. An
extracellular acidification predominantly increases the
inwardly directed monovalent cation conductance and
not that of divalent cations (262). However, it still remains to be determined whether the pH dependence of ion
channels contributes to their role in cell migration under
conditions of an increased acid load. To the best of our
knowledge, this aspect still awaits clarification. Unpublished observations from our laboratory indicate that acid-
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SCHWAB ET AL.
mediated inhibition of migration of HepG2 cells cannot be
overcome by a concurrent activation of TRPV1 channels.
This is in contrast to NHE1 whose activation in response to
an intracellular acidification by up to 0.5 pH units renders
migration of MDCK-F cells independent of pHi (287).
1. Na⫹/H⫹ exchanger NHE1
To date, 10 mammalian isoforms of NHE have been identified (276, 318). The most relevant NHE isoform for migrating cells is NHE1 (558) that is a ubiquitously expressed
housekeeping protein involved in maintenance of pHi and
cell volume (229). NHE1, in particular its intracellular
COOH-terminal tail, is the target for multiple binding partners and signaling cascades critical for its regulation and
subcellular localization (269, 380, 381). NHE1 regulates
(directed) migration of many different cell types (65, 86, 92,
108, 118, 126, 217, 287, 305, 313, 388, 443, 476, 481,
490, 514, 554). Usually, NHE1 inhibition (418) or knockdown impairs motility. There are several ways by which
NHE1 affects cell migration (see Refs. 555, 557, 558 for a
more detailed overview). These include effects on cell vol-
A
ume (see sect. IIIB), pHi (361), and thereby the assembly
and activity of cytoskeletal elements including focal adhesion proteins (see sect. IIID). It also regulates the pericellular pH at the cell surface and inside the glycocalyx (299,
556), anchors the cytoskeleton to the plasma membrane
(380), functions as a plasma membrane scaffold in the assembly of signaling complexes (380, 446), and modulates
gene expression (462, 637).
The contribution of NHE1 to migration relies on its polarized
subcellular distribution in migrating cells (see FIGURE 11).
NHE1 is concentrated at the leading edge of the lamellipodium (118, 197, 287, 305, 556) where it mediates local salt
and water uptake in collaboration with the Cl⫺/HCO3⫺ exchanger AE2 (287), Na⫹-K⫹-2Cl⫺ cotransporter NKCC1
(200, 527), aquaporin AQP1 (497), and possibly the Na⫹HCO3⫺ cotransporter NBC1 (518, 524) as well as carbonic
anhydrases (566). Changes of cell volume mediated by
NHE1 are also required for the chemotaxis of neutrophil
granulocytes. They rapidly swell upon stimulation with the
chemoattractant fMLP. This swelling can be partially inhibited by NHE1 blockade, or by replacement of extracellular
B
D
7.75
front
B16
7.65
*
7.55
intra
pHi
pHem
migration
(% of control)
7.6
NIH3T3
7.5
MDCK-F
7.4
100
50
MV3
rear end
7.3
7.2
extra
7.1
7.45
7.0
glycocalyx
7.35
6.9
DHPE-bound pHem indicator
0
WGA-bound pHem indicator
front
rear end
E
C
front
rear end
0
-0.02
50
-0.04
∆pHem
migration
(% of control)
100
-0.06
-0.08
-0.10
-0.12
membrane
-0.14
glycocalyx
0
20 µm
FIGURE 11. Polarization of NHE1 in migrating cells. A: topical application of the NHE inhibitor EIPA only
impairs migration of transformed renal epithelial MDCK-F cells when it is selectively applied to the cell front.
[From Klein et al. (287).] B and C: extracellular pH measurements (pHem) at the surface of the outer leaflet of
the plasma membrane of human melanoma cells. Inset indicates the position of the pH indicators (DHPE,
1,2-dihexaecanoyl-sn-glycero-3-phosphoethanolamine; WGA, wheat germ agglutinin). pHem is more acidic at
the cell front than at the rear part of the cell. The pericellular pHem gradient largely depends on NHE1 activity.
Upon washout of the NHE1 blocker Hoe642, pHem changes much more at the front than at the rear part of
the cell. [Modified from Schwab, Stock, and co-workers (299, 554, 556, 561), with permission from S.
Karger AG Basel.] D: NHE1 activity also generates an intracellular pHi gradient that is complementary to the
extracellular pHem gradient. pHi is more alkaline at the cell front of melanoma cells (MV3, B16), fibroblasts
(NIH3T3), and MDCK-F cells. [Modified from Martin et al. (361).] E: morphological correlate of the NHE1dependent extra- and intracellular pHem and pHi gradients. Immunohistochemistry reveals the concentration of
NHE1 at the leading edge of the lamellipodium of fibroblasts (arrows). [From Grinstein et al. (197), with
permission from Nature Publishing Group.]
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
Na⫹ (481, 490). While NHE1 blockade does not affect
chemokinesis, provided an intracellular acidification is prevented (217), it clearly inhibits fMLP-stimulated chemotaxis of neutrophils (481, 490). Thus stimulated migration in neutrophils requires an active NHE1, while random
migration of these cells can be maintained by compensatory
mechanisms independent of NHE1 activity. In MDCK-F
cells, Na⫹-HCO3⫺ cotransport (NBC) can partially substitute for the function of NHE1 (524). Inhibition of neutrophil chemotaxis by NHE1 inhibitors can be overcome with
hyposmolar media (481, 490). These findings lend further
support to the osmoregulatory role of NHE1 in cell migration.
The polarized distribution of NHE1 in migrating cells has a
profound impact on local pH homeostasis (FIGURE 11).
Despite the fact that glycolytic or ATP generating enzymes,
that also produce protons, are enriched within the lamellipodium (260, 302, 405, 586), the pHi of migrating cells is
more alkaline at the cell front than in their rear part (361).
Acid extrusion at the cell front, which is mediated by
NHE1, leads to a complementary extracellular pH gradient
at the surface with the more acidic pH at the cell front (556).
A similar NHE1-dependent intracellular pH gradient is observed during neurite outgrowth. pHi is more alkaline in
growth cones than in the cell soma (543). The pericellular
pH nanoenvironment at the cell surface is maintained by the
glycocalyx (299). Both intracellular and extracellular
NHE1-dependent pH gradients are required for cell migration (557) as described in more detail in section VA. They
promote the outgrowth of the lamellipodium by driving
actin polymerization and support the formation (at the cell
front) and release (at the rear part) of focal adhesion contacts to the extracellular matrix mediated by integrins (433,
623) (see also sect. IIB).
NHE1 and integrins are often colocalized at focal adhesion
sites (453). Functionally there is a reciprocal relationship
between integrins and NHE1. Integrins trigger signaling
cascades including the RhoA-ROCK cascade when binding
proteins of the ECM such as fibronectin that eventually lead
to increased NHE1 activity (4, 64, 247, 529, 587, 588).
Focal adhesion kinase (FAK) is one of the first proteins that
becomes phosphorylated in response to adhesion and triggers a signaling cascade promoting cell migration (387). Its
phosphorylation relies on the presence of NHE1 (587). Possibly, this is due to a direct effect of protons extruded by
NHE1. An NHE1-mediated acidification of the cell surface
activates neighboring integrins, i.e., causes an opening of
the integrin headpiece and thereby increases the affinity of
integrins for their ECM ligands (141, 321, 436, 561). Consequently, adhesion is stronger in an acid environment than
in an alkaline one, and migration is optimal at an intermediate adhesion strength (436, 554). Finally, NHE1 regulates
the secretion of cell matrix proteins such as fibronectin
(271).
NHE1 activity also affects the expression of genes that contribute to cell migration. The comparison of mouse muscle
fibroblasts (LAP cells) expressing either wt NHE1 or a
transport-deficient NHE1 revealed that NHE1 activity is
associated with the regulation of a number of genes that are
involved in the organization of the cytoskeleton, cell adhesion, and extracellular matrix assembly. Loss of NHE1 activity leads to downregulation of the expression of myosin
regulatory light chain, MMP-9, and merlin, a tumor suppressor protein and member of the ERM family. In contrast,
the expression of the actin severing and capping protein
gelsolin and that of a number of microtubule-related genes
such as Clip170, KIF4, kinesin light chain, and a dynein
heavy chain, are upregulated (462).
NHE1-dependent signaling cascades underlying directional
cell migration also include the primary cilium, a microtubule-based organelle emerging from the mother centriole
(500). The ciliary membrane contains the PDGFR␣ receptor for platelet-derived growth factor-AA (PDGF-AA) (93,
512), and binding of PDGF-AA to its receptor stimulates
NHE1 activity (642). When ciliary assembly in NIH3T3
fibroblasts and mouse embryonic fibroblasts is disturbed or
NHE1 is inhibited, chemotaxis towards PDGF-AA is absent, leading to a dramatic delay in wound healing, in vitro
and in vivo (511, 514).
NHE1 also elicits nonconductive functions in cell migration. NHE1 is a plasma membrane anchor for cortical actin
filaments (26, 119) and a scaffold for signaling complexes
(271, 632). In fibroblasts NHE1 attaches the cortical actin
cytoskeleton to the leading edge of the lamellipodia through
a direct association of its COOH-terminal domain with the
ERM (ezrin, radixin, moesin) family of actin-binding proteins that are also concentrated at the cell front. ERM proteins are substrates for Rho kinase 1 (ROCK1) (219) and
Nck-interacting kinase (27), both of which stimulate NHE1
activity (66, 587). Thus the colocalization of ERM proteins
and NHE1 appears to facilitate this reciprocal modulation
of cytoskeletal dynamics required for cell migration.
2. Monocarboxylate transporter
The monocarboxylate transporters (MCTs) mediate the
H⫹-coupled efflux of lactate, pyruvate, butyrate, acetate,
and propionate across the cell membrane (203). MCT1 to
-4 are widely expressed in many types of cancer (e.g., Refs.
295, 296, 598). They enable cancer cells to cope with the
hypoxic conditions they are often exposed to. Silencing of
an ancillary MCT subunit, CD147, inhibits MCT1 and
MCT4 function and reduces the malignant potential of pancreatic cancer cells (516). Along the same lines, silencing of
MCT4 impairs migration of the breast cancer cell line
MDA-MB-231 (168). Since MCT4 colocalizes with ␤1-integrin at the leading edges of the lamellipodia of migrating
retinal pigment epithelial (ARPE-19) and MDCK cells
(167) and since it is involved in regulating the cellular pH
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SCHWAB ET AL.
homeostasis, it is conceivable that MCT4 activity contributes to the special pH nanoenvironment at sites of focal
contacts (436, 556, 557) (see also sect. IIID). An alternative
mechanism proposes that lactate is released by tumor cells
(via MCT4), enters endothelial cells through MCT1, and
then triggers an autocrine NF-␬B/IL-8 pathway driving endothelial cell migration and tube formation (605). In addition, MCTs also affect cell migration by “nonconductive”
properties of their ancillary subunit CD147 which promotes cell invasion by inducing matrix-metalloproteases
(MMPs) such as MMP1–3, 9, 11, 14, and 15 (641).
B. Naⴙ-Kⴙ-2Clⴚ Cotransporter
The Na⫹-K⫹-2Cl⫺ cotransporter (NKCC1) contributes to
the regulation of cell volume and homeostasis of intracellular Cl⫺ concentration ([Cl⫺]i). NKCC1 was one of the first
transport proteins whose involvement in cell migration was
identified. Migration of keratocytes from Xenopus tadpoles
(32) and MDCK-F cells (527) is impaired in the presence of
the blockers piretanide, furosemide, and bumetanide. It was
hypothesized that Na⫹-K⫹-2Cl⫺ cotransport supports the
protrusion of the lamellipodium by inducing localized solute and water uptake, i.e., swelling at the cell front (527).
Two recent studies indeed revealed the enrichment of the
NKCC1 protein at the leading edge of the lamellipodium of
protruding PC12D cell neurite growth cones (404) or of
glioma (D54-MG and U87-MG) cells (200). NKCC1 activity stimulated by with-no-lysine kinase 3 (WNK3) (199) not
only leads to cell swelling but also to the intracellular accumulation of Cl⫺, which is the prerequisite for channel-mediated Cl⫺ efflux and volume loss. Interestingly, WNK3stimulated NKCC1 activity is required for glioma cell motility only in three-dimensional assays. This points out that
a fine-tuned, NKCC1-dependent alternation between very
local osmotic swelling and shrinkage is needed to guide
invadopodial protrusions through pores or a meshwork of
extracellular matrix proteins (620).
C. Naⴙ-Kⴙ-ATPase
The Na⫹-K⫹-ATPase is composed of a catalytic ␣ and a
regulatory ␤ subunit and an FXYD protein (173). The ␣
subunit mediates transport of Na⫹ and K⫹, and it binds
inhibitory cardiotonic steroids such as ouabain, digoxin,
digitoxin, and cardenolides (320, 336). The ␤ subunit is
required for normal Na⫹-K⫹-ATPase activity. Depending
on their expression, FXYD proteins regulate the kinetic
properties of the pump in a tissue-specific way (173). Not
all Na⫹-K⫹-ATPase molecules function as an ion-translocating pump. There is also a nonpumping pool of the Na⫹K⫹-ATPase (332) whose signal-transducing function is activated by cardiotonic steroids (330). It is restricted to caveolae, does not depend on changes of the intracellular Na⫹
and K⫹ concentrations, and involves among others the ty-
1894
rosine kinase Src, the PI3K/Akt pathway, and transactivation of the EGF receptor (290, 614).
Initially, the inhibition of keratocyte migration following
blockade of the Na⫹-K⫹-ATPase with ouabain was ascribed to the blockade of the pump function (32). However,
studies from the last 10 years revealed that the situation is
far more complex in that the nonconductive properties of
the Na⫹-K⫹-ATPase come into play too. In glioblastoma
and non-small-cell lung cancer, the ␣1 subunit of the Na⫹K⫹-ATPase is upregulated and colocalized with caveolin-1 in
lamellipodia (320, 382). Inhibition of the Na⫹-K⫹-ATPase
with the cardenolide UNBS1450 reduces migration in vitro.
Part of this effect was ascribed to an UNBS1450-induced intracellular ATP depletion and consecutive disorganization of
the actin cytoskeleton. The effects of UNBS1450 are independent of the pump function of the Na⫹-K⫹-ATPase since
[Ca2⫹]i and [Na⫹]i remain unchanged (320). In cytotrophoblast cells, inhibition of EGF-induced chemotaxis/
invasion by the endogenous cardiotonic steroid marinobufagenin correlates with reduced ERK1/2 phosphorylation (597). Regeneration of newt retina and lens, a
process involving migration of dedifferentiated progenitor cells, coincides with the upregulation of the ␣1 subunit of the Na⫹-K⫹-ATPase (606).
The ␤ subunit of the Na⫹-K⫹-ATPase is downregulated in
several invasive cancers and in tumor cell lines such as in
renal clear cell carcinoma (467) and Moloney sarcoma virus
(MSV)-transformed MDCK cells, respectively (468). The
causal link between Na⫹-K⫹-ATPase ␤-subunit and cell
motility was revealed by showing that restitution of the
␤-subunit strongly reduces migration of MSV-transformed
MDCK cells through interactions with the GTPase Rac1
(468) and proteins involved in PI3K signaling (24). The ␤2
isoform of the Na⫹-K⫹-ATPase, also known as “adhesion
molecule on glia” (AMOG), has been linked originally to
neuron-glia adhesion and cerebellar granule cell migration
(14). Its downregulation is linked to increased migration
and invasion of gliomas since its reexpression increases adhesion and reduces migration (532).
FXYD5 (also named dysadherin) has been correlated with
increased tumor progression and invasiveness. Capan-1
pancreatic cancer cells, expressing only a small amount of
endogenous FXYD5, can be transferred to a highly mobile
cell line with increased metastatic potential when they are
transfected with FXYD5 (537). Similarly, increased expression of FXYD5 in airway epithelial (385) or renal cell carcinoma cells (517) increases migration.
VI. PHYSIOLOGY AND PATHOPHYSIOLOGY
OF ION CHANNELS AND
TRANSPORTERS IN CELL MIGRATION
In this section we discuss two pathophysiological examples
of great clinical relevance. Research from the last decade
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
clearly revealed that targeting ion transport proteins represents a promising novel therapeutic strategy for the treatment of chronic inflammatory (autoimmune) diseases or
cancer. The beneficial effects of targeting ion transport proteins are at least in part due to their impact on the migratory
activity of the respective immune and tumor cells.
A. Immune Defense and Inflammation
Migration of cells of the innate and adaptive immune system is a prerequisite for their proper function. Invading
pathogens can only be cleared/phagocytosed when the respective immune cells have been recruited and have migrated to such a site of infection. Thus T cells display robust
motility in the lymph node, which was suggested to constitute a search strategy of T cells to locate and sample dendritic cells for antigens (384). Similarly, T-cell activation
following antigen presentation (383) and immune surveying of the brain by microglial cells (410) are highly dynamic
processes. Stated differently, when viewed from a hierarchical perspective, migration of immune cells occupies a superior position compared with other properties of immune
cells. Accordingly, primary immunodeficiencies that are often associated with an inability of immune cells to migrate,
result in increased susceptibility to (life threatening) infections and inability to repair tissue damage (413, 582).
Ca2⫹ signaling plays a crucial role in many additional facets
of the immune cell function such as phagocytosis, cytokine
secretion, and proliferation. Ca2⫹ signaling in turn strongly
relies on the fine-tuned activity of ion channels and transporters regulating the intracellular Ca2⫹ homeostasis. The
important contribution of ion channels, in particular,
KV1.3, KCa3.1, and CRAC channels (composed of Orai1
and STIM1), has been studied in great detail in lymphocytes. In fact, one of the earliest studies describing the involvement of K⫹ channels in cell proliferation was performed in T cells (114). KV1.3, KCa3.1, Orai1, and STIM1
cluster at the immunological synapse when T cells make
contact with an antigen-presenting cell. These channels
constitute a functional network (transportome) that has
a profound impact on intracellular Ca2⫹ signaling and
thereby regulates not only migration but also drives gene
expression, proliferation, and cytokine secretion (IL-2) of
T cells (see Ref. 59 for review). The physiological significance of ion channel signaling is underlined by the fact that
channel inhibition is highly effective in preclinical disease
models such as T cell-mediated colitis (124), inflammatory
skin diseases (406), asthma (49), type 1 diabetes mellitus or
rheumatoid arthritis (29), or EAE (349). It is this integrated
function of a distinct set of ion channels not restricted to a
selective role in T-cell migration that makes them such
promising therapeutic targets.
One further example illustrates that similar considerations
also apply to other cells of the immune system and to other
ion channels or transporters. Voltage-gated proton channels (VSOP/Hv1) play an important role in activated neutrophils. They are required for the generation of reactive
oxygen species during the respiratory burst (423) and maintenance of pH homeostasis during phagocytosis (397). By
sustaining the cell membrane potential during the respiratory burst, they also allow continued Ca2⫹ influx driving
cytoskeletal dynamics during migration (144).
B. Tumor Metastasis
Hypoxia (PO2 ⬍2.5 mmHg), usually coinciding with an
acidic extracellular pH, is a hallmark of solid tumors
(603). There is increasing evidence that an acidic interstitial pHe of tumors gives a selective advantage for tumor progression and metastasis. Thus lactate promotes
tumor cell migration but inhibits that of monocytes
(180). It drives large changes in gene expression and promotes increased invasion and metastasis (67). This involves
alterations of the ECM compartment through pH-dependent
upregulation of protease secretion/activation [e.g., matrix
metalloproteinases (MMPs), cathepsins], impaired function
of the antitumoral immune system (67, 389), or altered
growth factor/cytokine secretion (164, 635). In recent years
this concept was further refined by showing that pH regulatory transport proteins such as the Na⫹/H⫹ exchanger
NHE1 are tightly linked to the tumor-promoting effects of
extracellular acidity. Examples of NHE1-dependent processes relevant for tumor progression include tumor cellextracellular matrix interactions (436, 554), migration and
invasion (476, 554), MMP activity (57), secretion of ECM
proteins (271), and chemoresistance (312). In this context,
membrane-bound extracellular-facing carbonic anhydrase
(CA) isoforms also need to be considered. CAIX and CAXII
have been identified as markers of aggressive carcinomas
(87, 569). Tumor spheroids that express CAIX protect their
pHi efficiently at the expense of a more acidic pHe. Thus
expression of CAIX in conjunction with the relevant acidbase transporters (e.g., Na⫹-HCO3⫺ cotransport) would be
highly beneficial to cancer cells, by maintaining a pHi that is
favorable for their growth while creating at the same time a
hostile acidic environment for non-tumor cells (87). Tumors lacking extracellular CA isoforms may resort to transmembrane lactic acid secretion by MCT and/or Na⫹/H⫹
exchange for protecting their intracellular and acidifying
their extracellular milieu (67, 195, 557).
Recent discoveries of the function and expression of ion
channels and transporters in tumors clearly indicate that
tumor-associated alterations in ion homeostasis affect
essentially all transport proteins of cancer cells (178,
439, 460). This generalized alteration of members of all
major families of transport proteins in cancer cells is best
described with the concept of a tumor cell transportome.
The impact of an altered transportome is of crucial importance for almost all hallmarks of cancer. Every cell
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SCHWAB ET AL.
phenotype is characterized by a specific “ionic signature”
depending on the kinetics, magnitude, and subcellular
localization of ion signals. Due to the quantitative and
functional variations of ion channel activity in cancer,
this disease could then be classified as a “channelopathy.” The groundwork for this novel concept was laid in
the 1990s by recognizing that K⫹ channels (16, 491,
527), Cl⫺ channels (549), and voltage-gated Na⫹ channels (196) are required for tumor cell proliferation, migration, and invasion and are activated by integrins during cell adhesion. Another major breakthrough was the
discovery that the overexpression of a voltage-gated K⫹
channel, KV10.1, confers tumorigenicity on non-cancer
cells (438). Subsequently, members of the TRP channel
family entered the field as important players in cancer cell
pathophysiology. In fact, TRPM1 channels were originally identified as tumor suppressors, since their expression is high in benign nevi and low in metastatic melanoma (138).
Several important principles emerged from the studies on
ion transport in cancer. It is a general phenomenon that
the expression of proteins involved in ion transport
markedly differs between normal and the corresponding
tumor cells. Mutations of channels or transporters are
the exception (266). The correlation of ion channel/
transporter expression in tumor samples with the clinical
outcome of the respective cancer patient provides diagnostic and prognostic information that can be exploited
to improve patients’ quality of life. Many of the transport
proteins that are involved in tumor cell migration are
crucial for other hallmarks of cancer as well (460). Tumor cell proliferation and apoptosis are such examples.
The dual inhibition of tumor cell migration and proliferation by blocking, for example, KCa3.1 (151, 523) or
KV10.1 channels (6) would of course be very desirable.
On the other hand, inhibiting migration and apoptosis by
KV1.3 (570) or VRAC blockade (513) would not be advantageous, since it would favor the persistance of tumor cells.
These examples indicate that the multiplicity of cancer hallmarks controlled by a given transport protein requires careful
consideration of its therapeutic potential. However, such functional constraints of therapeutic options can be overcome
when cancer-specifically upregulated ion transport proteins
are exploited for targeted therapies. Alternatively, the combined inhibition of several transport proteins involved in complementary mechanisms may be beneficial.
VII. CONCLUSION AND OUTLOOK
Studying the function of ion channels and transporters in
cell migration is still a young field in cellular physiology
so that the number of studies mechanistically linking
transport proteins to the cytoskeletal motor of migration
is still limited. Nonetheless, the field is rapidly expanding
and produces an ever-growing list of ion transport pro-
1896
teins contributing to cell migration. Studies from the last
⬃15 years provided firm proof of the concept that transport proteins in the plasma membrane and possibly also
in intracellular membranes constitute integral components of the cellular migration machinery without which
the cytoskeletal migration motor or cell adhesion proteins do not function properly. That members of all major families of transport proteins have been linked to
migration of many different cell types is remarkable for
two reasons. First, it points towards the universal nature
of the involvement of ion transport proteins in cell migration. Second, it lends strong support to the concept of
a migration-related transportome. Importantly, “transportome” implies that in each cell a whole array of different ion channels and transporters is involved in controlling cell migration. Ion channels and transporters
control migration in multiple ways. These include their
core competencies as transport proteins as well as nonconductive properties. The transport function is also exploited in the regulation of the intracellular second messengers Ca2⫹ and pH. In addition, transport proteins and
receptor-activated signaling cascades modulate each
other reciprocally. We envision that transport proteins
impact on intracellular signaling in a very specialized and
localized way that is exemplified by TRPM2 channels
that are only required for neutrophil chemotaxis towards
fMLP but not CXCL2 (640). However, so far we are not
yet in a position to draw a conclusive picture on the role
of the transportome in cell migration and in particular in
disease states that are associated with “too much” migration.
The overwhelming majority of studies on members of the
transportome in cell migration investigates only the function of one transport protein in one particular cell type at
a time. Nonetheless, the multiplicity of these studies allows some generalization so that it can be taken for
granted that NHE1 and aquaporins play important roles
in cell migration. However, this approach, as valid as it
was in initially cataloging the relevant members of the
transportome, does not come close to reflecting the physiological complexity. NHE1 may serve as an example to
explain the future needs in the field to validate the integrated function of individual transportome members.
NHE1 is crucial in maintaining intra- and extracellular
pH homeostasis, and its role in cell migration also depends on the pH micorenvironment of the cell. Yet, so far
it is entirely unknown how NHE1 and its impact on pH
regulation affect the role of other pH-sensitive ion channels in cell migration such as KCa3.1 (445). To the best of
our knowledge, all studies revealing a role of KCa3.1 in
cell migration were performed at ⬃pH 7.4. However, in
tumor cells that usually express KCa3.1 channels, NHE1
and other pH regulatory proteins may produce a pH
microenvironment that is not necessarily permissive for
KCa3.1 activity. This example clearly indicates that fu-
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ION CHANNELS AND TRANSPORTERS IN CELL MIGRATION
ture studies need to address the mutual impact of members of the transportome on each other and the resulting
consequences for cell migration derived thereof. The
demonstration of the functional interdependence between KCC2 expression, GABA receptors, and voltagegated Ca2⫹ channels in cortical interneuron migration is
a good example for such studies (43). Thus a more integrative view on the transportome in cell migration combined with the use of the appropriate genetic mouse models and modern intravital or live-cell imaging technologies will be the next steps to further advance this new and
exciting field in cellular physiology.
ACKNOWLEDGMENTS
We thank all present and past members of the cell migration
laboratory without whose enthusiastic commitment much of
the work from our laboratory would not have been possible.
We thank Thomas Fortmann for preparing FIGURE 6A.
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Address for reprint requests and other correspondence:
A. Schwab, Institut für Physiologie II, Robert-Koch-Str.
27b, D-48149 Münster, Germany (e-mail: [email protected]).
15. Arcangeli A, Becchetti A. Complex functional interaction between integrin receptors
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GRANTS
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Barletta E, Wanke E, Olivotto M. Integrin-mediated neurite outgrowth in neuroblastoma cells depends on the activation of potassium channels. J Cell Biol 122: 1131–
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Our work was supported by Deutsche Forschungsgemeinschaft, European Commission (ITN “IonTraC”), IZKF
Münster, and IMF Münster.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the authors.
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