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TRENDS in Neurosciences Vol.25 No.8 August 2002
Lipid rafts in neuronal signaling
and function
Brian A. Tsui-Pierchala, Mario Encinas, Jeffrey Milbrandt and Eugene M. Johnson, Jr
Lipid rafts are plasma membrane microdomains rich in cholesterol and
sphingolipids, which provide a particularly ordered lipid environment. Rafts are
enriched in glycosylphosphatidylinositol (GPI)-anchored proteins, as well as
proteins involved in signal transduction and intracellular trafficking. In neurons,
lipid rafts act as platforms for the signal transduction initiated by several
classes of neurotrophic factors, including neurotrophins and glial-derived
neurotrophic factor (GDNF)-family ligands. Emerging evidence also indicates
that such rafts are important for neuronal cell adhesion, axon guidance and
synaptic transmission. Thus, lipid rafts are structurally unique components of
plasma membranes, crucial for neural development and function.
Brian A. Tsui-Pierchala
Mario Encinas
Dept of Molecular Biology
and Pharmacology,
Campus Box 8103,
Washington University
School of Medicine,
660 South Euclid Avenue,
St Louis, MO 63110, USA.
Jeffrey Milbrandt
Dept of Pathology,
Washington University
School of Medicine,
St Louis, MO 63110, USA.
Eugene M. Johnson, Jr*
Dept of Molecular Biology
and Pharmacology,
Campus Box 8103,
Washington University
School of Medicine,
660 South Euclid Avenue,
St Louis, MO 63110, USA.
*e-mail: ejohnson@
pcg.wustl.edu
Recently, lipid microdomains rich in sphingolipids
and cholesterol, also known as lipid rafts, have been
proposed as regions within plasma membranes that
are important for cellular signaling [1,2]. The unique
lipid composition of these rafts creates a more ordered
lipid environment than is found in the rest of the
plasma membrane [3,4], making them resistant to
non-ionic detergent extraction using Triton X-100 or
Brij 96 and giving rise to their alternative name of
detergent-resistant membranes (DRMs). The term
lipid raft originated from the observation that these
microdomains have a low buoyant density (and thus,
float during sucrose gradient centrifugation),
allowing their isolation.
The related membrane structures known as
caveolae are small (50–100 nm diameter) flask-shaped
invaginations of the plasma membrane, and analysis
of caveolae led to the concept of the lipid raft as a
biochemically distinct subregion of the plasma
membrane. Although caveolae are not clathrin-coated,
they are important regions for the internalization of
both transmembrane and cell surface proteins [2,5–7].
One characteristic of caveolae is the presence of
the caveolin proteins. Most researchers have found
that caveolae have a lipid constitution similar to
rafts: caveolae are rich in sphingolipids as well as
cholesterol, are detergent-resistant and float in
sucrose gradients [2,5,6]. However, not all cell types
have caveolae, and in cells that lack them lipid
microdomains that have similar biochemical
properties to caveolae are often named caveolaerelated domains (CRDs) [6]. Whether neurons have
caveolae, or even express caveolins to any significant
extent, has been controversial. Although there is
evidence indicating that caveolae are biochemically
distinct from CRDs or lipid rafts, this is disputed and
has been reviewed elsewhere [2,7–9]. We will,
therefore, not distinguish between caveolae, CRDs
and lipid rafts for the purposes of this review.
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One of the earliest observations that pointed to
lipid rafts as important structures for signal
transduction was their enrichment with signaling
molecules. These include transmembrane and
glycosylphosphatidylinositol (GPI)-anchored
receptors, as well as intracellular signaling
intermediates, such as trimeric and small GTPases,
Src family kinases (SFKs), lipid second messengers
and a variety of cytosolic signal transducers [7].
Most proteins are targeted to rafts by virtue of lipid
modifications, such as GPI or acyl anchors, which add
saturated chain lipids and, thus, allow the close
packing of proteins required for localization to lipid
rafts. Other molecules, such as the cytoplasmic
proteins Shc and Grb2, are presumably associated
with receptors that reside in rafts. Although some of
the transmembrane proteins – including Trk, LAT
(linker for activation of T cells) and PAG/Cbp
(phosphoprotein associated glycosphingolipidenriched membrane microdomains, also known as
Csk-binding protein) – are palmitoylated [10–12], the
motifs responsible for their targeting to rafts are
largely unknown. One complicating factor in the
analysis of which proteins and lipids constitute lipid
rafts is how the rafts are isolated. Most researchers
operationally define lipid rafts by detergent
insolubility and/or buoyancy on sucrose gradients. It
should be noted, however, that detergent extraction
removes some lipids and proteins from rafts, and the
extractability of proteins from rafts has even been
used to describe variability in lipid raft structure [13].
An important future direction for the study of lipid
rafts in neurons will be to use both biochemical and
microscopic techniques to visualize rafts.
Growing evidence indicates that rafts are crucial
for growth-factor signal transduction, cellular
adhesion, axon guidance, vesicular trafficking,
synaptic transmission and membrane-associated
proteolysis [2,7,14,15]. Most studies on lipid-raft
function have been performed on non-neuronal cell
types. Given the great complexity of neuronal
morphology, synaptic transmission and signal
transduction, lipid rafts are an appealing
mechanism by which neurons could regulate and
compartmentalize these events. Indeed, recent studies
point to the importance of rafts in neuronal function.
In this review we summarize the literature regarding
the involvement of lipid rafts in neuronal signal
transduction, focusing attention on growth factors,
cell adhesion, guidance and synaptic transmission.
0166-2236/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(02)02215-4
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TRENDS in Neurosciences Vol.25 No.8 August 2002
413
(a)
GF
GF
(b)
GF
GF
GF
GF
GF
GF
Lipid raft
Plasma membrane
GPI-anchored coreceptor
Growth factor
Raft-enriched proteins
Soluble coreceptor
Non-raft proteins
Phosphorylated tyrosine
Fig. 1. Neurotrophic factor signal transduction and lipid rafts.
(a) Growth factor receptor tyrosine kinases (RTKs) that are enriched in
lipid rafts, such as the epidermal growth factor receptor (EGFR),
platelet-derived growth factor receptor (PDGFR) and trks, are
activated and engage signaling molecules within rafts. (b) RTKs not
located in lipid rafts, such as Ret, can be recruited to them (right) –
either by their glycosylphosphatidylinositol (GPI)-anchored coreceptor
(far left), or by soluble coreceptor–ligand complexes via a different
mechanism (near left).
Neurotrophic factor signaling
The largest body of evidence indicating the
significance of lipid rafts in neuronal function is
in the realm of neurotrophic factor signaling.
Most growth factors signal by binding to, and
activating, receptor tyrosine kinases (RTKs) that
autophosphorylate tyrosine residues, thereby
creating binding sites for SH2 (Src homology 2)and PTB (phosphotyrosine-binding)-domain
containing proteins. These docking proteins form
signaling complexes with activated RTKs that
initiate multiple intracellular signaling cascades
[16,17]. Because signaling proteins are concentrated
in lipid rafts, the RTKs located in rafts are more
likely to engage signaling adaptors and enzymes
necessary for signal transduction. In support of
this concept, many RTKs – including the EGFR
(epidermal growth factor receptor) [18,19], PDGFR
(platelet-derived growth factor receptor) [9,20],
insulin receptor [21,22] and Trks [10,23–25] –
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RTKs
TRENDS in Neurosciences
are located in lipid rafts. Alternatively, RTKs that
are not located in lipid rafts, such as c-Ret,
translocate to rafts after or during activation [26,27].
Here we describe an example of each of these
mechanisms (Fig. 1).
TrkA signal transduction
Nerve growth factor (NGF) supports the survival of
sympathetic and some sensory neurons via activation
of its RTK, trkA [28,29]. A lower affinity receptor, p75,
contributes to high-affinity binding of NGF to trkA
and has additional independent functions, such
as in pro-apoptotic signaling [30–32]. In the
pheochromocytoma cell line PC12, both trkA and
p75 are enriched in rafts [10,24,25]. Localization of
trkA to lipid rafts enhances NGF-induced trkA
autophosphorylation, as well as its association and
phosphorylation of substrates such as SHC (Srchomologous and collagen-like protein) and PLCγ
(phospholipase Cγ) [10]. Conversely, drugs such as
methyl-β-cyclodextrin, which deplete plasma
membrane cholesterol (and therefore, disrupt
lipid rafts) decrease NGF-stimulated trkA
autophosphorylation by >50% [10,25]. This is similar
to other RTKs, such as PDGFR [9], in that lipid raft
depletion reduces ligand-dependent activation. Thus,
localization to lipid rafts enhances the signal output
of RTKs such as trkA. Although the mechanism for
414
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TRENDS in Neurosciences Vol.25 No.8 August 2002
this is unclear, two possibilities are that the
phosphatases that dephosphorylate activated RTKs
might normally be excluded from rafts, or that the
unique lipid content of rafts could promote the correct
folding necessary for optimal ligand binding or kinase
function. Consequently, in PC12 cells, but not in
NBL-S cells, cholesterol depletion also inhibits signal
transduction pathways downstream of trkA, such as
the MAPK pathway [25,26]. Whether raft disruption
inhibits trkA signaling because of the decrease in
trkA activity in the absence of rafts, or because closely
associated adaptor and signaling proteins are
mislocalized, or both, remains unresolved.
Whether PC12 cells (sympathetic neuron-like cells
in which most trkA signaling research has been
performed) have caveolae is controversial, and
probably depends on the PC12 line analyzed [10,24,25].
However, when caveolae have been identified,
trkA has appeared to be located within them [25].
In fact, caveolin can associate with both p75 and trkA
in PC12 cells, and caveolin inhibits trkA catalytic
activity both in vitro and in NGF-stimulated PC12
cells [24,33]. Like trkA, most raft-associated RTKs
such as EGFR [19] and PDGFR [34] are inhibited by
caveolin, consistent with other studies implicating
caveolin as a general inhibitor of signal transduction
in caveolae [35,36]. In contrast to its effect on
trkA-mediated NGF signaling, caveolin does not
inhibit processes downstream of p75-mediated
NGF signaling, such as ceramide production [24,33].
Because trkA inhibits p75-dependent ceramide
production, and because caveolin inhibits trkA,
caveolin could modulate cross talk between trkA and
p75 [37]. Therefore, the extent to which trkA
regulates p75 activity, and thus NGF signaling,
in neurons might depend upon the extent to which
they are located in lipid rafts or caveolae.
Ret signal transduction
The concept of rafts serving as platforms for signal
transduction arises not only from their enrichment in
signaling molecules, but also from the observation
that some receptors, especially in the immune
system, need to relocate to rafts after ligand binding
to initiate cellular responses [1]. Currently, the only
known example of such a mechanism in neurotrophicfactor signaling is glial-derived neurotrophic factor
(GDNF)-mediated activation of the Ret RTK [26].
GDNF signals via a receptor complex consisting of the
Ret and a GPI-anchored ligand-binding subunit,
GFRα1. As expected from its GPI anchorage, GFRα1
is located in rafts [38,39]. In the absence of GDNF,
GFRα1 and Ret do not associate with each other and
Ret is not present in lipid rafts. By contrast, upon
ligand stimulation, GFRα1–GDNF complexes recruit
Ret into lipid rafts [26]. Translocation to rafts is
essential for Ret function because manipulations that
render GFRα1 incapable of recruiting Ret into rafts
(e.g. use of a transmembrane-anchored GFRα1
chimera) or treatments that disrupt lipid rafts
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(e.g. cholesterol depletion) compromise downstream
signaling, survival and differentiation [26].
Functionally, co-stimulation of Ret with GDNF
and a soluble form of GFRα1 that lacks the GPI
anchor, in the absence of endogenous GFRα1
(i.e. trans signaling), diminishes downstream Ret
signaling and function [26]. This suggests that soluble
GFRα1 is unable to translocate Ret into rafts without
a GPI anchor. However, in a recent report, Paratcha
et al. have provided biochemical evidence that the
soluble GFRα1 coreceptor is capable of recruiting Ret
into lipid rafts [27]. In contrast to Ret translocation
by GPI-anchored GFRα1 or ‘cis’ stimulation
(i.e. by molecules within the same membrane),
trans-mediated recruitment of Ret into rafts occurs
with a slower time course and requires Ret catalytic
activity [27]. Interestingly, stimulation of Ret with
soluble or immobilized GFRα1 potentiates the
survival and neurite outgrowth elicited by GDNF in
neurons that also express GFRα1. This ‘cooperative’
signaling prolongs the localization and activation of
Ret in lipid rafts, thereby enhancing the functional
responses to GDNF [27].
In contrast to its effects on trkA activity,
lipid raft depletion by methyl-β-cyclodextrin
does not diminish GDNF-dependent Ret
autophosphorylation [26]. Therefore, translocation
to lipid rafts is required for signal transduction
downstream of Ret activation, but not for the
maintenance of Ret activity. This suggests that lipid
rafts constitute a favorable microenvironment for
the interaction of Ret with kinases and adaptor
proteins enriched in rafts. Consistent with this
hypothesis, Src family kinases, which are known to
be raft-resident proteins, have been identified as
crucial mediators of Ret signaling. More specifically,
p60Src associates with activated Ret in lipid rafts,
and Src activity is required for optimal GDNFmediated signaling and function [26,40]. FRS2
(fibroblast growth factor receptor substrate 2) is
another molecule that might account for raftdependent Ret signaling: it associates with Ret
specifically in lipid rafts, whereas SHC seems to be a
preferred target of Ret outside rafts [27].
In conclusion, lipid rafts augment RTK signaling,
by enhancing the RTK activity directly (as is true for
the RTKs constitutively located in rafts, such as
trkA), by providing a favorable microenvironment
for the engagement of required signaling molecules
(as in the case of Ret), or both. Because the majority
of research on neurotrophic factor signaling through
lipid rafts has been carried out using cell lines,
whether or not lipid rafts are required in neurons is
still largely unknown.
Cell adhesion and axon guidance
Stable contacts between neurons and their targets
are crucial for nervous system function. The
regulation of these contacts by local and longdistance tropic and trophic factors is vital for axon
Review
TRENDS in Neurosciences Vol.25 No.8 August 2002
guidance during development [41–43]. Growing
evidence supports an important function of lipid rafts
in these areas.
One observation that suggests that rafts are
required for cell adhesion is that many adhesion
molecules – such as TAG-1 (transiently expressed
axonal glycoprotein-1), NCAM-120 (neural cell
adhesion molecule), Thy-1 and F3/contactin – are
GPI-anchored and, thus, are located in rafts.
Increasing evidence suggests that adhesion molecules
do not only associate with other adhesion molecules,
but can also transmit intracellular signals.
For example, antibody cross-linking of adhesion
molecules such as TAG-1 promotes tyrosine
phosphorylation events within lipid rafts
(e.g. activation of the kinase Lyn) [44–46]. Conversely,
depletion of TAG-1 from lipid rafts, by blocking the
synthesis of glycosphingolipids, inhibits the ability
of TAG-1 to promote phosphotyrosine signaling
events [45]. Although the functional consequences
of signaling events activated by adhesion-receptor
cross-linking are unknown, localization to lipid rafts
appears to be a prerequisite. Furthermore, how the
cross-linking of GPI-anchored proteins (which do not
traverse the inner leaflet of the plasma membrane)
influences signaling events such as the activation of
Lyn (a protein that does not contact the outer plasma
membrane leaflet) is unknown. One possibility, as has
been suggested for molecules such as F3/contactin,
is that GPI-anchored adhesion molecules utilize
transmembrane signaling receptors to convey
intracellular signals [47].
Axon guidance and fasciculation, as well as neural
crest cell migration, are regulated by several classes
of axon guidance molecules, among which the Ephrin
ligands and their Eph RTKs are prominent [48,49].
One peculiarity of ephrins is that they are attached to
the plasma membrane either by a GPI linkage
(A ephrins) or by a transmembrane domain followed
by a short cytoplasmic tail devoid of any known
catalytic activity (B ephrins). Increasing evidence
indicates that ephrins promote ‘reverse’ signaling
(i.e. signaling that is triggered by binding to their Eph
‘receptors’), in addition to their function as ligands.
Interestingly, both A ephrin- and B ephrin-mediated
signaling events take place in lipid rafts.
Engagement of ephrin-A5 with EphA5 receptor
bodies increases the tyrosine phosphorylation of an
unidentified protein located exclusively in lipid rafts.
This phosphorylation event requires Fyn activity and
is concomitant with the recruitment of Fyn to these
domains [50]. At the cellular level, cross-linking of
ephrin-A5 induces the redistribution of the
cytoskeletal protein, vinculin, to focal adhesion
complexes and, along with additional cytoskeletal
signaling events, increases cellular adhesion [50].
Similar to the cross-linking of adhesion receptors,
the mechanism by which the extracellular and
intracellular ephrin signaling components
communicate in rafts is unknown.
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415
By contrast, ephrinB, which is also constitutively
located in lipid rafts, interacts with the GRIP
(glutamate-receptor-interacting protein) family of
adaptor proteins via its C-terminal tail, and recruits
these proteins to rafts [51,52]. GRIP proteins in turn
recruit into the ephrinB complex a serine/threonine
kinase that phosphorylates GRIP, an event thought to
initiate reverse signaling [51]. Importantly, the
regulation of this process is mediated by binding of
ephrinB to its Eph receptors because cross-linking
with EphB2-Fc results in the co-localization of
ephrinB and GRIP to large patches in the cellular
membrane [51]. Therefore, both cell adhesion
molecules and cell guidance molecules appear to
require lipid rafts for their correct localization within
the plasma membrane and for the downstream
signaling events just beginning to be identified.
Synaptic transmission
Recent studies have provided evidence that lipid rafts
contribute to neuronal excitability. Two areas in
which rafts contribute to synaptic transmission are in
the clustering and regulation of neurotransmitter
receptors and in the exocytotic process of
neurotransmitter release.
Although some neurotransmitter receptors (e.g. the
ionotropic glutamate receptor subunits NR1A [23] and
GluR1 [53]) are not biochemically located in lipid rafts,
other channels (e.g. the voltage-gated K+ channel
Kv2.1 [54], α7nAChR [55] and the GABABR receptor
[56]) are. α7nAChR colocalize with GM1 (a ganglioside
located exclusively in lipid rafts) in ciliary neurons
in vivo [55]. Localization of ion channels to lipid rafts
appears to vary depending upon the specific channel,
because even related channel subtypes within a single
family can have different solubility properties. For
example, the voltage-gated K+ channel Kv4.2 is not
located in lipid rafts, in contrast to Kv2.1 [54]. Lipid
rafts have been suggested to be a localization signal for
the targeting of proteins to axonal, but not to
somato–dendritic, membranes – but this is
controversial [57]. Several ion channels, including
α7nAChR and Kv2.1, as well as intracellular postsynaptic proteins such as GRIP, are located in rafts,
but are subcellularly located in dendrites, particularly
spines [51,54,55]. This indicates that targeting of
proteins to lipid rafts cannot in itself be an exclusive
axonal-targeting signal.
In addition to their potential importance for the
localization and clustering of ion channels, lipid rafts
are also required for specific channel properties.
For example, removal of Kv2.1 from lipid rafts by
cholesterol depletion significantly shifted the steadystate inactivation of Kv2.1, without altering the
activation kinetics or voltage sensitivity [54].
Therefore, lipid rafts might modulate voltage-gated
and neurotransmitter receptor activity in a manner
that has dramatic effects on neuronal excitability.
Whether the modulation of the electrophysiological
properties of Kv2.1 by its location in lipid rafts is
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TRENDS in Neurosciences Vol.25 No.8 August 2002
caused by specific lipid–protein interactions,
or reflects post-translational modifications
(e.g. phosphorylation) by proteins concentrated in
rafts, has yet to be resolved.
Neurotransmitter release is another aspect of
synaptic transmission that is regulated by lipid rafts.
Several of the key regulatory proteins involved in
synaptic vesicle fusion (syntaxin 1A, syntaxin 3,
SNAP-25 and VAMPs, which constitute the ‘core’
membrane fusion machinery) are biochemically
located in rafts [58] or raft-like clusters [59]. Other
proteins that associate with this core complex and are
required for membrane fusion (e.g. αSNAP and
nSec1) are not enriched in rafts [58]. This dichotomy
suggests that lipid rafts could regulate the spatial
organization of the membrane fusion machinery and,
perhaps, specific synaptic-vesicle-trafficking events.
Importantly, cholesterol depletion decreases the
amount of exocytosis and evoked dopamine release
from PC12 cells, supporting the importance of lipid
rafts in regulated exocytosis [58,59]. The specific
functions of lipid rafts in membrane fusion or
synaptic vesicle trafficking are, however, unknown.
Conclusions
Compelling evidence is emerging from neural cells
indicating the importance of lipid rafts in signal
transduction and synaptic transmission. However,
major questions remain regarding the exact role of
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An ‘oligarchy’ rules neural
development
David H. Rowitch, Q. Richard Lu, Nicoletta Kessaris and William D. Richardson
Recent reports show that Olig genes, which encode the basic helix–loop–helix
Olig transcription factors, are essential for development of oligodendrocytes.
Surprisingly, Olig function is also required for formation of somatic motor
neurons. These findings alter our views of how the oligodendrocyte lineage is
generated and raise further questions about the underlying developmental
relationships between neurons and glia.
Oligodendrocytes engage in complex interactions
with nerve cell bodies and axons in the CNS, notably
in the formation of myelin sheaths [1]. Myelin is an
elaborately structured proteolipid that serves to
insulate axons and facilitate rapid, saltatory
(jumping) nerve conduction, which is crucial for
nervous system function. When oligodendrocytes die
and myelin sheaths break down, as in diseases such
as multiple sclerosis, severe debilitation results. The
recent identification of transcription factors that
mark or determine key stages of oligodendrocyte
development has provided new genetic tools with
http://tins.trends.com
which to further dissect demyelinating disease and
other disorders of oligodendroglial cells.
Transcription factors as arbiters of oligodendroglial
cell fate
The roles of transcription factors in neuronal cell fate
specification in the CNS have been intensively studied
over the past decade (reviewed in Refs [2–4]) but cellintrinsic determinants of glial cell fate remain poorly
understood. Genes such as glial cells missing (gcm or
glide) and pointed encode transcription factors that
regulate formation of glia in Drosophila, but so far
there is no indication that their orthologues are
involved in development of oligodendrocytes or other
glia in vertebrates. Loss-of-function studies have
demonstrated roles for Sox10 [5] and Nkx2.2 [6] in the
maturation of oligodendrocyte precursors (OLPs) in
transgenic mice, but have left open the question of how
OLPs are initially specified.
0166-2236/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(02)02206-3