BBAMCR-17998; No. of pages: 11; 4C: 3, 5, 6, 7
Biochimica et Biophysica Acta xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
journal homepage: www.elsevier.com/locate/bbamcr
Review
TRP channels in calcium homeostasis: from hormonal control to
structure-function relationship of TRPV5 and TRPV6
Mark K.C. van Goor, Joost G.J. Hoenderop ⁎, Jenny van der Wijst ⁎
Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history:
Received 18 September 2016
Accepted 23 November 2016
Available online xxxx
Keywords:
Calcium
TRP channels
Structure
Hormones
a b s t r a c t
Maintaining plasma calcium levels within a narrow range is of vital importance for many physiological functions.
Therefore, calcium transport processes in the intestine, bone and kidney are tightly regulated to fine-tune the rate
of absorption, storage and excretion. The TRPV5 and TRPV6 calcium channels are viewed as the gatekeepers of
epithelial calcium transport. Several calciotropic hormones control the channels at the level of transcription,
membrane expression, and function. Recent technological advances have provided the first near-atomic resolution structural models of several TRPV channels, allowing insight into their architecture. While this field is still in
its infancy, it has increased our understanding of molecular channel regulation and holds great promise for future
structure-function studies of these ion channels. This review will summarize the mechanisms that control the
systemic calcium balance, as well as extrapolate structural views to the molecular functioning of TRPV5/6 channels in epithelial calcium transport.
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
The transient receptor potential (TRP) superfamily of ion channels
was founded with the characterization of its first member in Drosophila
melanogaster [1,2]. By that time, the locus had been the object of investigation for over a decade, following the discovery of a visually impaired
Drosophila mutant that exhibits a characteristic retinal electrical response to stimulation with bright light [3]. Soon after the discovery of
the initial trp locus in Drosophila, multiple mammalian trp orthologues
were reported in rapid succession. Currently, the TRP channel superfamily is made up of six mammalian subfamilies of ion channels; canonical (TRPC), melastatin (TRPM), vanilloid (TRPV), polycystin (TRPP),
ankyrin (TRPA) and mucolipin (TRPML), categorized based on sequence
homology [4–6]. Most members of the superfamily consist of six
transmembrane domains, a pore-forming loop between the fifth and
the sixth transmembrane domain, and large intracellular amino- and
carboxy-terminal regions that govern channel activity [7,8]. Functional
TRP channels require homo- or heterotetrameric organization of individual protein subunits. Heterotetrameric assembly adds new functional diversity to the TRP channel family and occurs both within and
between subfamilies, although channel formation with members of
the same subfamily is most commonly observed [9,10].
⁎ Corresponding authors.
E-mail addresses: [email protected] (J.G.J. Hoenderop),
[email protected] (J. van der Wijst).
TRP channels have myriad functions in cell biology, including migration, proliferation and survival. They play roles in carcinogenesis, immunological processes, tissue homeostasis, and are prominently present in
pathways of sensory transduction and electrolyte homeostasis [11–13].
All TRP channels are cation permeable channels and exhibit at least
some calcium conductance, exerting their function mostly by facilitating
spatiotemporal calcium signalling events [11]. The widespread presence
of TRP channels in sensory cascades corresponds with their ability to integrate multiple signals from the environment. The polymodal nature of
each channel tightly modulates the passage of calcium and other ions to
control timing and localization of the ion flux and downstream signalling processes [14,15]. As such, TRP channel activity is best viewed as
the sum of all activity-modulating factors at any given moment in
time. Finding common TRP channel activators however has proven to
be difficult, since the enormous diversity in physiological functions
and rather low sequence homology has led to subfamily- or even member-specific activators. However, there are a few shared characteristics
in the activation mechanisms for most TRP channels. A large fraction
can be activated directly by the binding of specific ligands, such as
vanilloid compounds, endogenous lipids, ATP, and select medications,
to binding pockets on the channel surface. Indirect activation that arises
downstream of receptor-mediated signalling, either via G-protein
coupled receptors (GPCR) or receptor tyrosine kinases, also controls
the activity of many TRP channels. Finally, several TRP channels are activated by biophysical mechanisms such as voltage, temperature and
stretch [14]. Interestingly, mechanical gating, caused by deformation
of the plasma membrane, was proposed recently as a universal
http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
0167-4889/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
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M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
activation mechanism for all TRP channels, although additional evidence is needed to substantiate this claim [16].
The polymodal activity profile of TRP channels makes them perfect
candidates to serve as regulated passageway through the otherwise impermeable plasma membrane of epithelial cells. Indeed, TRP channels
are increasingly recognized as key players in both ion transport and signalling processes in kidney epithelia [17]. Two TRP channels, TRPV5 and
TRPV6, have evolved into highly selective ion channels that partake in
the process of epithelial calcium transport, contributing significantly
to the maintenance of human calcium homeostasis [18]. A vital process,
since disturbances in calcium homeostasis can cause major health problems, including stone formation, bone disorders, tetany and electrocardiographic aberrations. Epithelial calcium transport is tightly regulated
to ensure that the combined processes of intestinal calcium absorption,
dynamic storage in bone and urinary excretion maintain serum calcium
levels within a narrow range (2.2–2.5 mmol/L).
In general, calcium transport over the epithelial barriers of intestine
and kidney can be divided into paracellular passive transport and transcellular active transport. The latter is a regulated process involving three
steps; apical entry of calcium into epithelial cells via TRPV5 or TRPV6,
immediate binding of calcium by calbindin-D9k and calbindin-D28K
which transport calcium to the basolateral membrane, and extrusion
through the plasma membrane calcium ATPases (PMCA1 and PMCA4)
and sodium-calcium exchanger isoform 1 (NCX1) [19]. TRPV5 and
TRPV6 are co-expressed in intestinal and renal epithelia and are able
to form heterotetrameric channels. TRPV5 is the main isoform in renal
epithelia, whereas TRPV6 is the main isoform in the intestines [20]. Of
note, TRPV5 expression is restricted to kidney while TRPV6 is more
ubiquitously expressed.
This review summarizes the current understanding of calcium homeostasis and the interconnected network of endocrine signals that
regulates calcium transport in bones, kidney and intestine. We pay special attention to the contributions of TRPV5- and TRPV6-mediated calcium transport, illustrating the characteristic polymodal TRP channel
activity profile. Afterwards, the focus shifts to recent advances in the
field of structural biology. The availability of structural density maps
for several members of the TRPV subfamily, most notably TRPV6, allows
for a deeper insight into the molecular mechanisms of epithelial calcium
transport. We provide an overview of the structural elements of TRPV
channels and how these may control selective calcium transport. Finally, this review also explores remaining gaps in our current knowledge
and indicates questions for future study.
2. Calcium homeostasis
2.1. Feedback is key; interacting calciotropic hormones and their effect on
mineral balance
Serum calcium levels are in a constant state of flux due to dietary
availability and the dynamic nature of calcium transport. When plasma
calcium levels change, the human body rapidly responds by tweaking
the relative contributions of the calciotropic hormones to reflect the
current calcium status. Almost immediately, parathyroid hormone
(PTH), vitamin D, fibroblast growth factor 23 (FGF23) and Klotho,
start to normalize plasma calcium levels by promoting calcium retention or wasting, dependent on the body's needs. Concerted negative
and positive feedback loops exist within this hormonal network, and
each member controls the activity of the others (Fig. 1). In short, PTH
and vitamin D are the body's most important defense mechanisms
against reduced calcium availability, and shift the equilibrium of calcium transport towards the plasma compartment. A decline in plasma
calcium levels activates the calcium-sensing receptor (CaSR) in the
parathyroid gland, which stimulates the release of PTH into the bloodstream. When present in the systemic circulation, PTH regulates calcium
transport processes in bones and kidneys and stimulates the conversion
of vitamin D to its biologically active form 1,25(OH)2D3 [21]. This
process takes place in the renal epithelial cells of the proximal tubule
and is catalyzed by 25(OH)D 1α-hydroxylase (CYP27B1), a member of
the cytochrome P450 enzyme system [22]. In turn, 1,25(OH)2D3 enters
the bloodstream and increases the plasma concentrations of calcium as
well as phosphate, by enhancing the expression of calcium and phosphate transporters in kidney, bone, and intestine (for an extensive
review, see [23]). As a feedback mechanism, 1,25(OH)2D3 loops
back on PTH and inhibits its expression. In addition, circulating
1,25(OH)2D3 also triggers bone cells to produce FGF23, a hormone
that is of central importance in phosphate homeostasis. FGF23 increases
renal phosphate excretion and decreases circulating 1,25(OH)2D3 levels
via two mechanisms: it reduces 1,25(OH)2D3 production by inhibiting
expression of CYP27B1 and it stimulates the turnover of vitamin D to
the inactive 24,25(OH)2D3 form, catalyzed by 1,25(OH)D-24-hydroxylase (CYP24A1) [24]. The feedback loop between 1,25(OH)2D3 and
FGF23 allows crosstalk between bone and kidney and maintains bone
integrity. Furthermore, FGF23 controls calcium homeostasis by regulating the expression of PTH in the parathyroid gland [24].
2.2. The stimulatory effects of PTH on plasma calcium levels
In healthy adults, around 98% of all calcium is present as hydroxyapatite crystals within bone tissue. Osteoblasts stimulate the storage of
calcium through the formation of new bone matrix whereas osteoclasts
release calcium by breaking down bone matrix. Within bone, PTH
enhances the efflux of calcium (and phosphate) to the blood compartment through two separate mechanisms. First, the presence of PTH
shifts the equilibrium for bone mineralization and increases the calcium
flux from the mineralized compartment to the extracellular fluid compartment, through a yet unknown mechanism [25]. At the same time,
PTH upregulates the expression of RANKL (receptor activator of nuclear
factor kappa-B ligand), a member of the TNF cytokine family, within
osteoblast cells [26]. These cells then excrete RANKL, which binds its
receptor (RANK) on the surface of osteoclasts, stimulating their differentiation and bone-resorbing activity to free up even more calcium
and phosphate from the bone matrix. Expression of the TRP channels;
TRPV4, TRPV5 and TRPV6 has been confirmed in osteoclasts, where
they play roles in bone architecture and osteoclast differentiation and
activity [27]. Mutations in TRPV4 are the underlying cause of several
forms of congenital skeletal dysplasia disorders in which endochondral
osteogenesis is affected [28]. To this date, no bone disorders have been
linked to mutations in TRPV5 or TRPV6, although their respective
knockout mouse models do display bone abnormalities. Trpv5−/−
mice have reduced trabecular and cortical bone thickness, combined
with an increase in osteoclast numbers and osteoclast surface area
[29]. Contrary to what these observations suggest, Trpv5−/− osteoclast
cultures display significantly lower bone resorption levels compared
to wild type [30]. A study with human bone marrow-derived osteoclast
cultures proposed TRPV5 as a mediator of RANKL signaling, showing
that siRNA knockdown of TRPV5 almost completely abrogates the
calcium influx that is required for the final stages of osteoclast differentiation [27,31]. A later study demonstrated that TRPV5 modulation
of RANKL-signaling is further regulated by estrogen, a pathway that
may play a critical role in postmenopausal osteoporosis [32]. The phenotype of Trpv6−/− mice is highly similar to the Trpv5 knockout, with
increased osteoclast numbers and surface area, and reduced osteoclast
activity [33]. Remarkably, no changes in bone microarchitecture or mineralization were observed in a mouse model with a non-functional
Trpv6D541A/D541A mutant, which suggests that additional factors mediate
the bone phenotype observed in full TRPV6 knockout mice [34]. In conclusion, the role of TRPV6 in bone metabolism and osteoclast function is
not yet fully elucidated and warrants further exploration. Additionally,
the exact molecular link between RANKL signaling and TRPV5-mediated calcium entry into osteoclasts is an interesting target for future
research.
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
3
Fig. 1. Hormonal control of calcium homeostasis. A decrease in circulating calcium stimulates the parathyroid gland to release PTH, which in turn causes an increase in blood calcium levels
by stimulating osteoclastic bone resorption, renal calcium reabsorption and renal production of 1,25(OH)2D3, to increase intestinal calcium absorption. Subsequently, 1,25(OH)2D3
stimulates FGF23 production in bone, which then inhibits PTH production from the parathyroid gland and inhibits 1,25(OH)2D3 production in the kidney in a negative feedback loop.
Calcium is absorbed from the food in the epithelial cells of the intestine (enterocytes). This occurs by TRPV6, which is under the control of vitamin D signalling. In the distal convoluted
tubule of the kidney, calcium is reabsorbed at the luminal (pro-urine) side via TRPV5, transported to basolateral side by calbindin-D28K and extruded to the blood compartment by
NXC and PMCA. Signalling pathways activated by the PTH receptor, vitamin D receptor, and FGF receptor control the TRPV5 expression and activity. In addition, αKlotho can stabilize
TRPV5 at the plasma membrane. Calcium handling in bone occurs via PTH and RANKL signalling which govern osteoclast-mediated bone resorption. Abbreviations: 1,25(OH)2D3, active
vitamin D; FGF23, fibroblast growth factor 23; FGFR, FGF receptor; NCX1, sodium-calcium exchanger 1; PMCA1b, plasma membrane calcium ATPase 1b; PTH, parathyroid hormone;
PTH1R, PTH receptor; RANK, receptor activator of nuclear factor kappa-B; RANKL, receptor activator of nuclear factor kappa-B ligand; RXR, retinoid X receptor; VDR, vitamin D receptor.
Within the kidney, binding of PTH to its receptor PTH1R enhances
reabsorption of calcium by increasing the expression of several
calciotropic genes in the distal part of the nephron, most notably
TRPV5 [35]. In addition, PTH1R can induce rapid changes in calcium
transport through activation of intracellular signaling cascades [36].
On one hand, it activates phospholipase C that cleaves phospholipid
phosphatidylinositol 4.5-bisphosphate (PIP2) into diacylglycerol
(DAG) and inositol 1,4,5-triphosphate (IP3), which in turn activate protein kinase C (PKC). PKC phosphorylation on TRPV5 was shown to inhibit channel retrieval from the plasma membrane as a result of
decreased caveolae-mediated endocytosis of the channels [37]. On the
other hand, PTH1R signaling increases the concentration of intracellular
cyclic AMP (cAMP) which activates protein kinase A (PKA). De Groot et
al. have shown that the molecular target of PTH-mediated PKA activation in TRPV5 is threonine 709 (T709). In a follow-up study, they postulated a model in which calmodulin negatively regulates channel activity
until PTH stimulation of PKA leads to phosphorylation of T709, causing a
loss of calmodulin binding and an increase in single channel activity
[38]. Direct PKC/PKA phosphorylation of TRPV6 has not been reported
to our knowledge, although it has been shown to play an indirect role
in channel regulation [39,40]. It is important to note that PKC and PKA
are downstream of a very large group of surface receptors called the
GPCRs. As a result of this, many other factors that bind GPCRs, such as
bradykinin, plasmin and tissue kallikrein also regulate TRPV5 in various
ways. Taken together, current literature suggests that PKC/PKA phosphorylation modulates TRPV5 (and TRPV6) activity in a site-specific
manner, capable of either stimulating or inhibiting the channel based
on where phosphorylation took place, and further study is needed to
understand how phosphorylation balances the channel activity in
healthy and pathogenic situations.
2.3. Vitamin D and intestinal calcium absorption:
The hormone 1,25(OH)2D3 binds the vitamin D receptor/retinoic X
receptor (VDR/RXR) heterodimer, which translocates to the nucleus to
regulate transcription of a multitude of genes involved in calcium homeostasis, carcinogenesis and immunology [41]. The physiological
function of 1,25(OH)2D3 and the VDR/RXR mainly involves upregulation
of calcium transporting genes in the intestines and, to a lesser extent, in
bone and kidney. Our current understanding is that paracellular transport is the predominant form of calcium absorption in the intestines
and that the transcellular pathway contributes little (8–10%) to intestinal calcium absorption under physiological conditions. However, the
transcellular pathway can be significantly enhanced in times of calcium
depletion, predominantly in the duodenum [42]. There is a strong correlation between transcellular calcium transport efficiency over the intestinal epithelial layer and the TRPV6 and calbindin-D9k expression levels
along the various segments of the intestines, pointing to a central role
for these proteins in the transcellular pathway. Furthermore, it was
shown that TRPV6 and calbindin-D9k expression is heavily dependent
on 1,25(OH)2D3 stimulation [43]. Thus, researchers accepted a model
in which TRPV6 and calbindin-D9k facilitate transcellular calcium transport through the enterocyte under the governance of 1,25(OH)2D3.
More recently, this concept has been challenged by the generation of
Trpv6 and calbindin-D9k knockout mice. Surprisingly enough, both
mouse models retain their ability to significantly increase transcellular
intestinal calcium absorption in response to a low calcium diet, albeit
considerably weaker in Trpv6−/− mice [44,45]. Furthermore, treating
these mice with 1.25(OH)2D3 stimulates duodenal transcellular calcium
transport to levels that are comparable to wildtype littermates [44]. On
the other hand, a double knockout mouse (Trpv6−/−/calbindin-D−/−
9K )
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
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does exhibit significantly reduced levels of duodenal calcium transport
after 1,25(OH)2D3 treatment [44]. Moreover, intestine-specific Trpv6
overexpression in Vdr knockout mice can rescue their abnormal bone
phenotype and low serum calcium by significantly enhancing intestinal
calcium absorption [46].
In conclusion, several groups have proven the redundancy of TRPV6
in 1,25(OH)2D3-stimulated calcium absorption, while others have demonstrated a niche for TRPV6 within the transcellular calcium pathway.
Most likely, the exact conditions that require active involvement of
TRPV6 are still incompletely characterized. In the future, researchers
should focus on deciphering the molecular mechanisms that control intestinal calcium transport through TRPV6, especially since altered
TRPV6 expression has been linked to several intestinal cancers and inflammatory diseases like Crohn's disease [47,48].
In the kidney, 1,25(OH)2D3 also plays a role in calcium reabsorption,
specifically on the active transcellular transport pathway in the distal
convoluted tubule. Here, 1,25(OH)2D3 increases the expression of several calcium transporting genes, including TRPV5, Calbindin-D28K and
NCX1. A knockout mouse of Cyp27b1 displayed reduced expression of
all above-mentioned genes and treatment with 1,25(OH)2D3 restored
expression to wild type levels [49]. Because TRPV5 is the gatekeeper
of transcellular calcium reabsorption in the kidney, one would expect
a significant reduction in its expression in the absence of VDR signaling.
Surprisingly, even though renal calcium reabsorption is impaired in Vdr
null mice, only Calbindin-D9K expression is reduced [23].
into high affinity FGF23 receptors [57]. Since αKlotho is required for the
affinity change that allows the binding of FGF23 to its receptor, FGF23
target organs are restricted to tissues that co-express αKlotho and
FGFRs, such as the kidney. This is confirmed by the notion that kidney-specific klotho knockout mice show a comparable phenotype as
the systemic klotho knockout mice, exhibiting hyperphosphatemia, hypercalcemia, and increased 1,25(OH)2D3 and FGF23 levels [58]. Interestingly, αKlotho is mainly expressed in the distal tubules, while renal
phosphate reabsorption and vitamin D activation primarily take place
in the proximal tubules [59]. Therefore, it is still a matter of debate
how αKlotho mediates its effect on phosphate homeostasis. Within calcium homeostasis, αKlotho contributes to the suppression of PTH and
1,25(OH)2D3 through its action with FGF23. Furthermore, soluble
αKlotho directly increases renal calcium reabsorption by stabilizing
TRPV5 at the epithelial membrane [60]. Chang et al. demonstrated βglucuronidase activity for secreted αKlotho that affects the glycosylation of TRPV5 [60]. A later study proposed that αKlotho has sialidase activity and demonstrated that removal of end-standing sialic acids on
glycosylated TRPV5 could enhance the binding of galectin, resulting in
cell surface retention of the channel [61]. Recently, it is also suggested
that membranous αKlotho can promote trafficking of TRPV5 through
intracellular modification of the glycan [62].
3. The building blocks of TRPV5 and TRPV6
3.1. Connecting two worlds requires a special type of ion channel
2.4. The FGF23-Klotho axis as a coordinator of electrolyte transport in bone
and kidney:
The classical concept of calcium homeostasis, with the PTH-vitamin
D axis as the sole regulator, does not fully capture the intricacies of calcium handling by the human body. Multiple studies have highlighted
the contributions of an additional hormone axis, consisting of FGF23
and Klotho, which regulates urinary calcium and phosphate excretion,
and provides a negative feedback loop that modulates the actions of
PTH and vitamin D [24]. FGF23 increases renal phosphate excretion
via transcriptional downregulation of the SLC34a1 gene encoding for
the sodium-dependent phosphate transporter, NaPi2a, as well as regulating its expression at the apical membrane of the proximal tubule of
the kidney [50,51]. As for renal calcium transport, it was shown that
FGF23 regulates membrane trafficking of TRPV5 in the distal convoluted
tubule [52].
FGF23 is produced by osteoblasts and osteocytes and is a member of
the endocrine subfamily of FGFs. Production of FGF23 is primarily regulated by circulating levels of 1,25(OH)2D3. This notion is based on the
observation that mice treated with 1,25(OH)2D3 exhibit a rapid increase
in FGF23 serum levels, while Vdr−/− mice have undetectable serum
levels of FGF23 [53]. Indeed, 1,25(OH)2D3 is responsible for a rapid induction of FGF23 transcription, likely via vitamin D response elements
in close proximity to the FGF23 gene [54]. Some VDR-independent
mechanisms are also reported to affect the expression of FGF23, such
as local bone regulation by other FGFs, dietary phosphate, and PTH
levels. However, their relative contributions to FGF23 expression levels
compared to 1,25(OH)2D3 is rather small, except for pathological situations [54]. In any case, FGF23 regulation is complex and multifactorial
and exact molecular mechanisms that govern FGF23 expression in pathophysiology are important questions for future research.
All members of the endocrine subfamily signal via FGF-receptors and
require a co-factor from the Klotho family to initiate binding and downstream signaling. The anti-aging hormone αKlotho was identified as the
obligatory co-factor for FGF23 [55]. It is a single-pass transmembrane
protein, mainly expressed in the renal distal convoluted tubules and in
the brain choroid plexus. However, klotho has two isoforms and exists
either as a full-length transmembrane protein or as a smaller soluble
factor that is present in serum [56]. The full-length form causes a conformational change in the c-isoforms of the FGFRs 1, 3, and 4, to turn them
In the sections above, we illustrated the involvement of multiple organs, several hormones and many additional molecules that have to interact to keep serum calcium levels balanced. Multiple factors are
usually present at the same time, which all signal to produce a combined calcium transport response. As mentioned before, the TRP channel polymodal activity profile allows them to fulfill a prominent role
in these pathways. The question remains, how do they do it? In the sections below, the structure-function relationships of TRPV5 and TRPV6
will be discussed. Understanding how the channels are build contributes to a better understanding of their function and may shed new
light on their roles within calcium homeostasis.
3.2. Overall architecture of the channels
Similar to all TRP channels, TRPV5 and TRPV6 form functional
channels through tetramerization of individual subunits. The recently
resolved structures of TRPV1, TRPV2 and TRPV6 provide the first
steps towards understanding the structure-function of TRP channels
[63–65]. From a front view, the channel follows a clover-like shape
with a transmembrane stem and four petals, tightly connected and facing down into the cytoplasm to form the intracellular domain (Fig. 2).
Six alpha helices make up the transmembrane domain that crosses the
lipid bilayer. The loop between the fifth and the sixth transmembrane
domain faces inwards and downwards and is called the pore-forming
loop. The extracellular domain of the pore-forming loop governs the
ion selectivity of the channel and attracts cations towards the channel
pore. It is thought that the carboxy-terminal regions are fixed to the interior of the channel, hanging down into the cytoplasm. This orientation
allows post-translational modifications and protein binding. The aminoterminal region of each subunit forms one of the petals of the clover and
has been linked to channel assembly and allosteric modulation of the
pore region.
3.3. The channel assembly domain; stabilizing properties via interacting
elements.
An intricate mesh of interactions, both within and between subunits,
facilitates the assembly of four subunits into tetrameric ion channels.
Researchers initially focused on the ankyrin repeat domain (ARD) in
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
A
5
B
C
Fig. 2. Ion channel architecture of TRPV5 homology model. A) Front view of the TRPV5 tetramer with each subunit depicted in a different colour. B) Diagram of the TRPV5 domain
organization, with colours matching the structural model in C. C) Front view of one TRPV5 subunit with different channel domain.
the TRPV amino-terminus as the possible channel assembly domain
(Fig. 3) since this highly conserved helix-loop-helix structure is often involved in protein-protein interactions. Indeed, the ARD of TRPV6 plays a
role in channel assembly, as in vitro data demonstrated that amino-terminal constructs of the channel are able to interact with the full-length
channel. More specifically, the third ankyrin repeat and third finger loop
appear essential, as deletion of these regions significantly affected the
pull-down efficiency [66]. Using a similar pull-down experiment, the
pre-ARD region of the TRPV5 amino terminus (residues 1–75) was
linked to channel assembly [67]. A later study demonstrated that deletion of the first 38 amino acids produces non-functional channels,
while tetramerization is unaffected [68]. Furthermore, the authors identified two residues, glutamine (Q31) and aspartic acid (D34), which are
essential for correct folding and proper channel function [68]. A similar
loss of channel function has been reported for TRPM8, upon deletion of a
small part of the amino terminus (amino acids 40–86). Immunostaining
of insect cells transfected with TRPM8 deletion mutants showed a defective pattern of retention in the endoplasmic reticulum and loss of
staining at the plasma membrane [69]. However, deletion of the pre-
ankyrin repeat regions of TRPV1 and TRPV4 does not affect localization
of these channels [70]. These contrasting results could be explained by
differences in TRP channel folding mechanisms (pre-ARD alpha helix).
Additionally, amino-terminal sorting motifs or binding sequences may
direct the TRP channels to the plasma membrane. This has recently
been shown to play a role in the membrane targeting of TRPC4 [71].
While these early functional studies provided some insight into
TRPV5 and TRPV6 channel assembly, they are unfit to elucidate the
structural mechanisms that underlie this process. Instead, structural
analysis of the channels was needed to identify the inner workings of
the channels. Crystallization of the ARD has been performed for most
of the TRPV members. The structural models revealed that the six tandem copies of the TRPV ARD produce a somewhat atypical ARD that deviates from the canonical structure at two sites. Firstly, the finger loop
lengths of the TRPV ARD are considerably longer, which is particularly
noticeable in the third finger loop [72,73]. In addition, there is an unusual twist between the fourth and the fifth ankyrin repeat [72]. Within
these crystallization studies, purified TRPV5 and TRPV6 ARDs were unable to self-assemble in solution, suggesting that additional structures
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
6
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
A
B
Fig. 3. Channel assembly domain. A) TRPV5 model depicting the structural link between the amino-terminal helix, the ankyrin repeats (ARDs), the (ARD-S1) linker domain, and the pre-S1
helix that is important for channel assembly. B) Zoomed view of the amino terminal domain showing the localisation of the two residues (Q31 and D34) that were found to play a role in
channel folding and assembly.
are involved. Thus, crystal structures were unfit to study channel assembly, though they have shed new light on various ligand binding sites and
possible mechanisms for channel regulation.
Recently, advances in the fields of cryo-electron microscopy and Xray crystallography have allowed researchers to construct structural
density maps for several members of the TRPV subfamily, using (close
to) full-length constructs. The first example was TRPV1, revealing a
near-atomic resolution of the channel structure [63]. Here, the authors
showed that multiple domains within the amino- and carboxy termini
interact to facilitate channel assembly. Within every individual subunit,
there are two domains present that are involved in channel assembly;
the ARD and the amino-terminal linker domain. The latter connects
the ARD to the first transmembrane domain (S1) and is comprised of
a beta-hairpin structure with two beta-sheets (B1 and B2), a helixturn-helix and the pre-S1 helix (Fig. 3). One additional beta-sheet, originating from a six-residue stretch on the carboxy terminus, interacts
with the beta-hairpin structure in the linker to form a three-stranded
beta-sheet. This interaction between the linker domain and the carboxy
terminus within an individual subunit may provide stability and direct
the carboxy terminus towards the center of the channel, where it is
available for binding by intracellular factors. Every subunit interacts
with its neighbors through tangles of hydrogen bonding, salt bridging
and hydrophobic interactions. All structural density maps of TRPV channels show interactions between the third ankyrin repeat, fourth ankyrin
repeat and third finger loop of one subunit with the three-stranded
beta-sheet in the linker domain of a neighboring subunit [63–65,74].
Two residues that produce the sharp turn within the amino-terminal
part of the beta-hairpin, a glycine and a proline, are present in all members of the TRPV subfamily, further underlining the importance of the
connection between the ARD and the three-stranded beta sheet structure of the linker.
Of particular interest is that both structural density maps of TRPV1
and TRPV2 lack the pre-ARD amino terminus, which is either removed
to improve stability or because no density was detected for this stretch,
suggesting a lack of order in this region [63,64,74]. In contrast, the recent structural map for TRPV6 reveals a pre-ARD alpha helix at the center of the channel assembly domain, confirming the observations made
in the earlier TRPV5 amino-terminal deletion study [65,68]. This helix
likely connects to the three-stranded beta sheet by salt bridges and hydrogen bonds, which involves residue D34 (Fig. 3). Besides these connections, residue Q31 in the pre-ARD alpha helix also interacts with
the pre-S1 helix of a neighboring subunit. The TRPV6 structural density
map also demonstrates a carboxy-terminal hook that connects the
carboxy terminus of one subunit to the pre-ARD alpha helix of a neighboring subunit [65]. These two features appear to be specific to TRPV5
and TRPV6 channels, based on the lack of density for the pre-ARD
alpha helix in TRPV1 and TRPV2 maps [64,75]. The functional implications of these diversities in TRPV architecture are not yet investigated
to our knowledge, but may contribute to the specific roles of TRPV5
and TRPV6 in epithelial calcium transport.
3.4. The permeation pathway; calcium selectivity is the first step
The pore of TRPV channels bears resemblance to that of other ion
channels, such as voltage-gated potassium, sodium and calcium channels [76]. It consists of a selectivity filter, a hydrophobic cavity and a
lower gate. One of the unique features of TRPV5 and TRPV6 is their highly calcium-selective conductivity profile, with a PCa/PNa N 100 as opposed to a conductivity profile of PCa/PNa ≈ 1–10 for the other TRPV
channels [77]. When aligning the sequences of the selectivity filters it
becomes clear that TRPV5 and TRPV6 are different from the others (TV/I-I-D in TRPV1–4 versus G-M/L-G-D/E in TRPV5/6). Nilius and colleagues have shown that the unique calcium selectivity of TRPV5 and
TRPV6 could be abolished by substituting the aspartic acid at position
542 in TRPV5 (D542A) and 541 in TRPV6 (D541A) into an alanine. The authors also observed an overall decrease in calcium permeation and a loss
of voltage-dependent magnesium block, whilst monovalent permeation
remained intact [78]. This data is further supported by the TRPV6 structural map, which shows that the side chains of D541 point towards the
pore axis to form a 4.6 Å ring of negative charges. This ring is believed
to attract cations to the pore entrance [65]. Further analysis of the
TRPV6 outer pore region by Saotome and colleagues yielded three phenylalanines just downstream of D541 that may restrict the flexibility of
D541, creating a rather rigid outer pore structure. This is in contrast
with the more flexible outer pore structure of TRPV1 that only contains
one phenylalanine [63,65]. Not surprisingly so, since ligand-mediated
TRPV1 activation requires a higher degree of flexibility that enables
the selectivity filter to change between open and closed conformations.
Further illustrating the increased flexibility of the TRPV1 outer pore region compared to TRPV5/6 is the ability of TRPV1 to allow passage of
large cations after long-lasting agonist activation, referred to as pore dilation. Indeed, the restricting methionine of the TRPV1 selectivity filter,
together with the pore turret, a stretch of amino acids in the outer pore
domain, are involved in this process [79]. The pore turret, which is located upstream of the selectivity filter in TRPV1, is a highly divergent region within the TRPV sequence and is completely absent from TRPV5/
6. Therefore, sequence differences in the selectivity filter, coupled with
the flexibility of the outer pore may explain the differences in calcium
selectivity between TRPV5/6 and TRPV1–4.
Saotome and colleagues have proposed a mechanism of calcium permeation, in which there are three binding sites. Site 1 (D541) requires
constitutive binding of calcium due to charge clashes between the
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
D541 side chains in the absence of the cation. This suggests a so-called
‘knock-off’ mechanism, in which a high local calcium concentration
can push (and replace) a calcium ion from site 1. Subsequently, this
ion moves to site 2 located just below the filter, which might serve as
an intermediate hatch for site 3. This latter site is the lower gate
(M577) as outlined below, which is thought to be the final step towards
calcium entry into the cell. Some caution is needed here, as TRPV6 was
resolved in closed conformation and information concerning channel
gating remains incomplete [65].
3.5. The lower gate; mechanisms that open the channel
Below the selectivity filter, the TRPV pore area widens into a large
hydrophobic cavity (13 Å in TRPV6), which is capable of holding a hydrated calcium ion. Similar to voltage-gated sodium channels, the hydrophobic cavity is connected to the lipid bilayer via fenestrations,
that may allow small molecules or lipids to enter the cavity and regulate
channel activity [65,80]. Beyond the hydrophobic cavity, the helices of
the sixth transmembrane domains cross, resulting in a constriction
point at residue 577 in TRPV6 (Fig. 4). Here, the side chains of the methionine (M577) protrude into the central pore axis, similar to the equivalent methionine in TRPV2 [64,65]. In contrast, the lower gate in TRPV1
is formed by an isoleucine (I679) that is located closer to the selectivity
filter and further away from the S6 helix bundle crossing. It is thought
that allosteric opening of the lower gate plays a pivotal role in TRPV
channel activation. The most extensively studied method of opening
the lower gate is ligand-induced gating of TRPV1. Binding of the strong
vanilloid compound resiniferatoxin (RTx) to a binding pocket close to
the S4–S5 linker causes a rotation in the pore helix that opens the
lower gate. Capsaicin, a vanilloid compound found in chili peppers,
also binds the vanilloid pocket and rotates the pore helix. Interestingly,
this rotation follows a direction opposite to RTx and causes a less pronounced opening of the channel pore (9.3 Å diameter for RTx compared
to a 7.6 Å diameter for capsaicin) [81].
7
While vanilloid sensitivity is not conserved in other TRPV channels it
could be induced in TRPV2 via two point mutations in the vanilloid
binding pocket, suggesting that gating via the S4–S5 linker is still
present [82]. In fact, channel gating via the S4–S5 linker appears a likely
candidate for most TRP channels, albeit initiated differently. Zubcevic
et al. proposed a mechanism in which opening of the TRPV2 lower
gate involves subsequent rotation of the ARD domain, linker domain
and the carboxy-terminal TRP domain, which then rotate the pore
helix to open the gate in a similar way as vanilloid activation in TRPV1
[64]. This idea is strengthened by two recent papers on TRPV4 and
TRPV3 human disease mutations. Mutations in TRPV4 are known to
cause peripheral neuropathy and/or skeletal dysplasia, likely caused
by an increased single channel activity of mutant channels. Based
on a TRPV4 homology model, authors showed a bond between residues W733 in the TRP domain and L596 in the S4–S5 linker that
keeps the channel gate closed [83]. A specific human mutation,
L596P, distorts the structure and weakens the L596–W733 bond,
thereby destabilizing the closed state of the channel and explaining
the increased channel activity and the observed gain-of-function
phenotype [83]. In addition, specific genetic variants of the TRP box
tryptophan and S4–S5 linker in TRPV3 (W692G and G573C respectively) have been linked to congenital Olmsted syndrome [84,85].
They were shown to cause significantly enhanced channel activity,
suggesting the mutations disturb the so-called gating bond and
hold the channel in an open state [84].
When looking at the TRPV6 structural density map, it is important to
note the absence of density for the S4–S5 linker. This has created a conformation in which the pore domains of every subunit are packed
against the S1–S4 domain of the same subunit [65]. In contrast, the
TRPV1 and TRPV2 structures reveal a conformation in which the pore
domains are swapped, meaning that they are packed against the S1–4
of a neighboring subunit [63,64]. Hence, for the constitutively opened
channels TRPV5 and TRPV6, the lower gate may not be opened in exactly the same fashion, and little is known about their gating mechanism,
both on the structural and functional level.
Fig. 4. Permeation pathway of TRPV channels. Schematic overview of the channel pore depicting a constriction at the upper and lower pore area. Aligned sequences of these regions
(selectivity filter and the lower gate) of all TRPV channels are shown on the right. Blue box indicates the residue comprising the upper constriction point playing a role in ion
selectivity. Orange box indicates the proposed constriction point at the lower gate. Asterisk indicates complete sequence conservation. (For interpretation of the references to colour in
this figure legend, the reader is referred to the web version of this article.)
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
8
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
3.6. The carboxy terminus; regulatory role in channel function
The most important hallmark of TRP channels is located in the
carboxy-terminal domain: the TRP domain (Fig. 2). This is a ~25-residue
long region that follows just after the sixth transmembrane segment
and contains a highly conserved TRP box that is involved in channel
gating [86–89].
The exact functional role of the TRP box in TRPV5 and TRPV6 is unclear, but is proposed to act as a sensor for PIP2 levels [90]. Regulation
of TRP channel gating by PIP2 and other phosphoinositides is widespread throughout the superfamily and differences in observed effects
may be due to experimental conditions or channel-specific lipid interactions (reviewed in [91]). It is thought that TRPV5/6 are stabilized by
PIP2, which helps the channels to maintain their open conformation. A
recent paper shows that a glycine residue (G488), located between the
fourth and fifth transmembrane domain, is involved in PIP2 affinity for
TRPV5 and TRPV6 [92]. However, the exact association between PIP2
and the TRP box, as well as the structural implication of PIP2 binding
to its binding pocket in TRPV5/6 are not yet identified. Structurally,
the TRP domain adopts an alpha-helical turn that runs at the inner
membrane-cytosol interface beneath the fourth and fifth transmembrane domains. It lies between the helix-loop-helix linker domain and
the pre-S1 helix (Fig. 2) that connects to the ARD, and can thereby function as a structural communication bridge between the transmembrane
helices and the intracellular domains. From the TRPV1 structure it
seems that tight interactions between these domains are important
for opening of the lower gate, a phenomenon that is not observed in
the TRPV2 and TRPV6 structural maps [64,65,81]. In addition, it was
recently shown that lipid interactions in close proximity to the TRP
domain stabilize the TRPV1 channel in a resting state, by occupying
the binding pocket for antagonist binding [93]. Future studies should
focus at reconstituting TRPV5 and TRPV6 into liposomes or nanodiscs,
small lipid compartments, to determine the channel regulation by
lipid binding.
After the TRP domain, the carboxy-terminal tail forms an extended
loop, consisting of a beta sheet that interacts with a beta sheet of the
linker domain and a motif in the ARD (Fig. 2) [65,74,81]. This suggests
that the carboxy terminus supports the linker domain in regulating subunit assembly and in linking intracellular and transmembrane regions.
Its role in channel assembly has long been postulated based on several
reports demonstrating in vitro multimerization of purified recombinant
carboxyl tails of TRPV1 [94,95]. Furthermore, it has been demonstrated
for several TRPV channels that (partial) truncation of the carboxy terminus affects the functional properties of the channel [96–98]. For TRPV5,
the carboxy terminus plays an important role in channel regulation.
First, Yeh et al. demonstrated that TRPV5 can be inhibited by intracellular acidification, suggested to occur through a conformational change of
the pore helix leading to closing of channel via narrowing the upper
gate (selectivity filter). They identified lysine 607 (L607) as binding residue for protons [99]. Second, the PKA phosphorylation site T709 of
TRPV5 was identified as regulatory mechanism for parathyroid hormone stimulation. Phosphorylation of T709 was shown to increase the
open probability of single TRPV5 channels [100]. Third, TRPV5 plasma
membrane abundance can be stabilized by tissue kallikrein, a serine
protease in the kidney, that activates PKC signaling resulting in phosphorylation of serine 564 (Ser654) in the TRPV5 carboxy terminus
[101]. Fourth, the TRPV5 (and TRPV6) carboxy terminus was shown to
interact with a several auxiliary proteins, like S100A10, NHERF2, and
Rab11a, that affect channel trafficking and stabilization [102–104]. Another study demonstrated the importance of a positively charged histidine residue (His712) in the regulation of TRPV5 function. Substitution
into a negative aspartic acid (H712D) resulted in delayed internalization
and thereby increased TRPV5 channel activity [96]. Finally, the carboxy
terminus is involved in calcium-dependent channel inactivation. This
was shown to depend on two calcium-sensing motifs, one between residues 650 and 653 and the other in the last 30 residues [105]. Calcium-
dependent inactivation was shown to rely on calmodulin binding to the
carboxy terminus [38]. A tryptophan residue close to the T709 phosphorylation site was shown to be essential as mutation into alanine (W702A)
resulted in loss of calmodulin binding and excessive Ca2+ influx. Similar
calmodulin binding motifs have been shown for other TRPV channels
[106–109]. A recent paper even states that PIP2, calmodulin, and
Ca2 +-binding protein S100A1 compete for the same binding site in
TRPV1, and thereby influence channel regulation [108]. However, to decipher the gating mechanism of calmodulin-dependent calcium inactivation in TRPV5, more structural data are required. Resolving the
complete structure of the carboxy terminus has proven difficult so far,
likely due to the high flexibility in this region.
4. Conclusions
Our knowledge of the molecular regulation of renal calcium handling has greatly increased over the past decade. Specific hormones
(PTH, Vitamin D, and FGF23/Klotho) control the calcium balance
through an intricate network of feedback mechanisms within the
bone-kidney-parathyroid system. While PTH and vitamin D have long
been established as calciotropic hormones, the more recent discoveries
on the roles of FGF23 and αKlotho have revolutionized our understanding of calcium homeostasis and established a PTH-vitamin D-FGF23
axis. While significant progress is made in elucidating the pathophysiology and genetic abberations of these hormones in calcium-related disorders, challenges remain regarding the cause-and-effect mechanism.
The relationship between the hormones is complex and multi-organ
feedback together with the kinetics of each hormone complicates
isolation of specific roles. Current studies focus on combining different
(inducible) knockout mouse models to define how each hormone exerts its effects on other hormones and ultimately provide a full understanding of their role in maintaining the mineral balance. This will
contribute to the diagnosis and treatment regime for diseases associated
with calcium disturbances.
Recent technological breakthroughs transformed the single particle
cryo-EM to a powerful technique for the high-resolution structure determination of large membrane proteins. The structural study of the
first TRPV channels (TRPV1, TRPV2, and TRPV6) has provided valuable
mechanistic insight into the architecture of these ion channels, and delivered novel ideas on channel permeation and gating mechanisms.
Though, the conclusions can be controversial as the conformation of
the ion channel is sensitive to the experimental conditions and interaction regions are likely dependent on the activation state of the channel.
This emphasizes the need for corroborating the structural results with
functional analysis of the ion channel.
With this review, we provide an up-to-date overview of the clinical
and fundamental knowledge on calcium homeostasis and in particular,
on the molecular functioning of the epithelial calcium channels TRPV5
and TRPV6.
Transparency Document
The Transparency document associated with this article can be
found, in online version.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
We thank Hanka Venselaar for generating the TRPV5 homology
model, based on the TRPV6 structure (PDB file 5IWP). This work was
financially supported by the Netherlands Organization for Scientific
Research (VENI 863.13.010 and VICI 016.130.668), and by the Dutch
Kidney Foundation (160KK25).
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
References
[31]
[1] C. Montell, K. Jones, E. Hafen, G. Rubin, Rescue of the Drosophila phototransduction
mutation trp by germline transformation, Science 230 (1985) 1040–1043.
[2] C. Montell, G.M. Rubin, Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction, Neuron 2
(1989) 1313–1323.
[3] D.J. Cosens, A. Manning, Abnormal electroretinogram from a Drosophila mutant,
Nature 224 (1969) 285–287.
[4] C. Harteneck, T.D. Plant, G. Schultz, From worm to man: three subfamilies of TRP
channels, Trends Neurosci. 23 (2000) 159–166.
[5] D.E. Clapham, L.W. Runnels, C. Strübing, The TRP ion channel family, Nat. Rev.
Neurosci. 2 (2001) 387–396, http://dx.doi.org/10.1038/35077544.
[6] K. Venkatachalam, C. Montell, TRP channels, Annu. Rev. Biochem. 76 (2007)
387–417, http://dx.doi.org/10.1146/annurev.biochem.75.103004.142819.
[7] D.E. Clapham, TRP channels as cellular sensors, Nature 426 (2003) 517–524, http://
dx.doi.org/10.1038/nature02196.
[8] B. Nilius, G. Owsianik, The transient receptor potential family of ion channels, Genome Biol. 12 (2011) 218, http://dx.doi.org/10.1186/gb-2011-12-3-218.
[9] M. Schaefer, Homo- and heteromeric assembly of TRP channel subunits, Pflugers
Arch. 451 (2005) 35–42, http://dx.doi.org/10.1007/s00424-005-1467-6.
[10] W. Cheng, C. Sun, J. Zheng, Heteromerization of TRP channel subunits: extending
functional diversity, Protein Cell 1 (2010) 802–810, http://dx.doi.org/10.1007/
s13238-010-0108-9.
[11] K.S. Vrenken, K. Jalink, F.N. van Leeuwen, J. Middelbeek, Beyond ion-conduction:
channel-dependent and -independent roles of TRP channels during development
and tissue homeostasis, Biochim. Biophys. Acta 1863 (2016) 1436–1446, http://
dx.doi.org/10.1016/j.bbamcr.2015.11.008.
[12] T. Smani, G. Shapovalov, R. Skryma, N. Prevarskaya, J.A. Rosado, Functional and
physiopathological implications of TRP channels, Biochim. Biophys. Acta 1853
(2015) 1772–1782, http://dx.doi.org/10.1016/j.bbamcr.2015.04.016.
[13] J.G.J. Hoenderop, R.J.M. Bindels, Calciotropic and magnesiotropic TRP channels,
Physiology (Bethesda) 23 (2008) 32–40, http://dx.doi.org/10.1152/physiol.
00039.2007.
[14] I.S. Ramsey, M. Delling, D.E. Clapham, An introduction to TRP channels, Annu. Rev.
Physiol. 68 (2006) 619–647, http://dx.doi.org/10.1146/annurev.physiol.68.040204.
100431.
[15] J.K. Hilton, P. Rath, C.V.M. Helsell, O. Beckstein, W.D. Van Horn, Understanding
thermosensitive transient receptor potential channels as versatile polymodal cellular sensors, Biochemistry 54 (2015) 2401–2413, http://dx.doi.org/10.1021/acs.
biochem.5b00071.
[16] C. Liu, C. Montell, Forcing open TRP channels: mechanical gating as a unifying activation mechanism, Biochem. Biophys. Res. Commun. 460 (2015) 22–25, http://
dx.doi.org/10.1016/j.bbrc.2015.02.067.
[17] V. Tomilin, M. Mamenko, O. Zaika, O. Pochynyuk, Role of renal TRP channels in
physiology and pathology, Semin. Immunopathol. 38 (2016) 371–383, http://dx.
doi.org/10.1007/s00281-015-0527-z.
[18] J.G.J. Hoenderop, B. Nilius, R.J.M. Bindels, Calcium absorption across epithelia, Physiol. Rev. 85 (2005) 373–422, http://dx.doi.org/10.1152/physrev.00003.2004.
[19] S. Boros, R.J.M. Bindels, J.G.J. Hoenderop, Active Ca(2+) reabsorption in the
connecting tubule, Pflugers Arch. 458 (2009) 99–109, http://dx.doi.org/10.1007/
s00424-008-0602-6.
[20] T. Nijenhuis, J.G.J. Hoenderop, R.J.M. Bindels, TRPV5 and TRPV6 in Ca(2+) (re)absorption: regulating Ca(2+) entry at the gate, Pflugers Arch. 451 (2005) 181–192,
http://dx.doi.org/10.1007/s00424-005-1430-6.
[21] A. Murayama, K. Takeyama, S. Kitanaka, Y. Kodera, Y. Kawaguchi, T. Hosoya, et al.,
Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha,25(OH)2D3 in intact animals, Endocrinology 140 (1999) 2224–2231, http://dx.doi.org/10.1210/
endo.140.5.6691.
[22] K. Takeyama, S. Kitanaka, T. Sato, M. Kobori, J. Yanagisawa, S. Kato, 25Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis, Science 277
(1997) 1827–1830.
[23] S. Christakos, P. Dhawan, A. Verstuyf, L. Verlinden, G. Carmeliet, Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects, Physiol. Rev. 96
(2016) 365–408, http://dx.doi.org/10.1152/physrev.00014.2015.
[24] J.E. Blau, M.T. Collins, The PTH-vitamin D-FGF23 axis, Rev. Endocr. Metab. Disord.
16 (2015) 165–174, http://dx.doi.org/10.1007/s11154-015-9318-z.
[25] R.V. Talmage, H.T. Mobley, Calcium homeostasis: reassessment of the actions of
parathyroid hormone, Gen. Comp. Endocrinol. 156 (2008) 1–8, http://dx.doi.org/
10.1016/j.ygcen.2007.11.003.
[26] J.C. Huang, T. Sakata, L.L. Pfleger, M. Bencsik, B.P. Halloran, D.D. Bikle, et al., PTH differentially regulates expression of RANKL and OPG, J. Bone Miner. Res. 19 (2004)
235–244, http://dx.doi.org/10.1359/JBMR.0301226.
[27] L. Lieben, G. Carmeliet, The involvement of TRP channels in bone homeostasis, Front.
Endocrinol. (Lausanne) 3 (2012) 99, http://dx.doi.org/10.3389/fendo.2012.00099.
[28] H.A. Leddy, A.L. McNulty, F. Guilak, W. Liedtke, Unraveling the mechanism by
which TRPV4 mutations cause skeletal dysplasias, Rare Dis. 2 (2014),
e962971http://dx.doi.org/10.4161/2167549X.2014.962971.
[29] J.G.J. Hoenderop, J.P.T.M. van Leeuwen, B.C.J. van der Eerden, F.F.J. Kersten,
A.W.C.M. van der Kemp, A.-M. Mérillat, et al., Renal Ca2 + wasting,
hyperabsorption, and reduced bone thickness in mice lacking TRPV5, J. Clin. Invest.
112 (2003) 1906–1914, http://dx.doi.org/10.1172/JCI19826.
[30] B.C.J. van der Eerden, J.G.J. Hoenderop, T.J. de Vries, T. Schoenmaker, C.J. Buurman,
A.G. Uitterlinden, et al., The epithelial Ca2+ channel TRPV5 is essential for proper
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
9
osteoclastic bone resorption, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 17507–17512,
http://dx.doi.org/10.1073/pnas.0505789102.
E. Chamoux, M. Bisson, M.D. Payet, S. Roux, TRPV-5 mediates a receptor activator
of NF-kappaB (RANK) ligand-induced increase in cytosolic Ca2+ in human
osteoclasts and down-regulates bone resorption, J. Biol. Chem. 285 (2010)
25354–25362, http://dx.doi.org/10.1074/jbc.M109.075234.
F. Chen, Y. Ouyang, T. Ye, B. Ni, A. Chen, Estrogen inhibits RANKL-induced osteoclastic differentiation by increasing the expression of TRPV5 channel, J. Cell.
Biochem. 115 (2014) 651–658, http://dx.doi.org/10.1002/jcb.24700.
L. Lieben, B.S. Benn, D. Ajibade, I. Stockmans, K. Moermans, M.A. Hediger, et al.,
Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis, Bone 47 (2010) 301–308, http://dx.doi.org/10.
1016/j.bone.2010.04.595.
B.C.J. van der Eerden, P. Weissgerber, N. Fratzl-Zelman, J. Olausson, J.G.J.
Hoenderop, M. Schreuders-Koedam, et al., The transient receptor potential channel TRPV6 is dynamically expressed in bone cells but is not crucial for bone mineralization in mice, J. Cell. Physiol. 227 (2012) 1951–1959, http://dx.doi.org/10.1002/
jcp.22923.
M. van Abel, J.G.J. Hoenderop, A.W.C.M. van der Kemp, M.M. Friedlaender, J.P.T.M.
van Leeuwen, R.J.M. Bindels, Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone, Kidney Int. 68 (2005) 1708–1721, http://dx.doi.
org/10.1111/j.1523-1755.2005.00587.x.
R.J. Bindels, A. Hartog, J. Timmermans, C.H. van Os, Active Ca2+ transport in primary cultures of rabbit kidney CCD: stimulation by 1,25-dihydroxyvitamin D3
and PTH, Am. J. Phys. 261 (1991) F799–F807.
S.-K. Cha, T. Wu, C.-L. Huang, Protein kinase C inhibits caveolae-mediated endocytosis of TRPV5, Am. J. Physiol. Renal Physiol. 294 (2008) F1212–F1221, http://dx.
doi.org/10.1152/ajprenal.00007.2008.
T. de Groot, N.V. Kovalevskaya, S. Verkaart, N. Schilderink, M. Felici, E.A.E. van der
Hagen, et al., Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone, Mol. Cell. Biol. 31 (2011) 2845–2853, http://dx.doi.
org/10.1128/MCB.01319-10.
D. Al-Ansary, I. Bogeski, B.M.J. Disteldorf, U. Becherer, B.A. Niemeyer, ATP modulates Ca2+ uptake by TRPV6 and is counteracted by isoform-specific phosphorylation, FASEB J. 24 (2010) 425–435, http://dx.doi.org/10.1096/fj.09-141481.
L.A. Borthwick, A. Neal, L. Hobson, V. Gerke, L. Robson, R. Muimo, The annexin 2S100A10 complex and its association with TRPV6 is regulated by cAMP/PKA/CnA
in airway and gut epithelia, Cell Calcium 44 (2008) 147–157, http://dx.doi.org/
10.1016/j.ceca.2007.11.001.
J.W. Pike, M.B. Meyer, The vitamin D receptor: new paradigms for the regulation of
gene expression by 1,25-dihydroxyvitamin D(3), Endocrinol. Metab. Clin. North
Am. 39 (2010) 255–69– table of contents 10.1016/j.ecl.2010.02.007.
F. Bronner, Mechanisms and functional aspects of intestinal calcium absorption, J.
Exp. Zool. A Comp. Exp. Biol. 300 (2003) 47–52, http://dx.doi.org/10.1002/jez.a.
10308.
S.J. Van Cromphaut, M. Dewerchin, J.G. Hoenderop, I. Stockmans, E. Van Herck, S.
Kato, et al., Duodenal calcium absorption in vitamin D receptor-knockout mice:
functional and molecular aspects, Proc. Natl. Acad. Sci. U.S.A. 98 (2001)
13324–13329, http://dx.doi.org/10.1073/pnas.231474698.
B.S. Benn, D. Ajibade, A. Porta, P. Dhawan, M. Hediger, J.-B. Peng, et al., Active intestinal calcium transport in the absence of transient receptor potential vanilloid type
6 and calbindin-D9k, Endocrinology 149 (2008) 3196–3205, http://dx.doi.org/10.
1210/en.2007-1655.
T.E. Woudenberg-Vrenken, A.L. Lameris, P. Weissgerber, J. Olausson, V. Flockerzi,
R.J.M. Bindels, et al., Functional TRPV6 channels are crucial for transepithelial
Ca2+ absorption, Am. J. Physiol. Gastrointest. Liver Physiol. 303 (2012)
G879–G885, http://dx.doi.org/10.1152/ajpgi.00089.2012.
M. Cui, Q. Li, R. Johnson, J.C. Fleet, Villin promoter-mediated transgenic expression of
transient receptor potential cation channel, subfamily V, member 6 (TRPV6) increases intestinal calcium absorption in wild-type and vitamin D receptor knockout
mice, J. Bone Miner. Res. 27 (2012) 2097–2107, http://dx.doi.org/10.1002/jbmr.1662.
S. Huybers, M. Apostolaki, B.C.J. van der Eerden, G. Kollias, T.H.J. Naber, R.J.M.
Bindels, et al., Murine TNF(DeltaARE) Crohn's disease model displays diminished
expression of intestinal Ca2+ transporters, Inflamm. Bowel Dis. 14 (2008)
803–811, http://dx.doi.org/10.1002/ibd.20385.
V. Lehen'kyi, M. Raphaël, N. Prevarskaya, The role of the TRPV6 channel in cancer, J.
Physiol. Lond. 590 (2012) 1369–1376, http://dx.doi.org/10.1113/jphysiol.2011.
225862.
J.G.J. Hoenderop, O. Dardenne, M. van Abel, A.W.C.M. van der Kemp, C.H. van Os,
R.S. Arnaud, et al., Modulation of renal Ca2+ transport protein genes by dietary
Ca2+ and 1,25-dihydroxyvitamin D3 in 25-hydroxyvitamin D3-1alpha-hydroxylase knockout mice, FASEB J. 16 (2002) 1398–1406, http://dx.doi.org/10.1096/fj.
02-0225com.
O. Andrukhova, U. Zeitz, R. Goetz, M. Mohammadi, B. Lanske, R.G. Erben, FGF23 acts
directly on renal proximal tubules to induce phosphaturia through activation of
the ERK1/2-SGK1 signaling pathway, Bone 51 (2012) 621–628, http://dx.doi.org/
10.1016/j.bone.2012.05.015.
T. Shimada, H. Hasegawa, Y. Yamazaki, T. Muto, R. Hino, Y. Takeuchi, et al., FGF-23
is a potent regulator of vitamin D metabolism and phosphate homeostasis, J. Bone
Miner. Res. 19 (2004) 429–435, http://dx.doi.org/10.1359/JBMR.0301264.
O. Andrukhova, A. Smorodchenko, M. Egerbacher, C. Streicher, U. Zeitz, R. Goetz,
et al., FGF23 promotes renal calcium reabsorption through the TRPV5 channel,
EMBO J. 33 (2014) 229–246, http://dx.doi.org/10.1002/embj.201284188.
Y. Inoue, H. Segawa, I. Kaneko, S. Yamanaka, K. Kusano, E. Kawakami, et al., Role of
the vitamin D receptor in FGF23 action on phosphate metabolism, Biochem. J. 390
(2005) 325–331, http://dx.doi.org/10.1042/BJ20041799.
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
10
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
[54] M.R. Haussler, G.K. Whitfield, I. Kaneko, R. Forster, R. Saini, J.-C. Hsieh, et al., The
role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine
axis, Rev. Endocr. Metab. Disord. 13 (2012) 57–69, http://dx.doi.org/10.1007/
s11154-011-9199-8.
[55] H. Kurosu, Y. Ogawa, M. Miyoshi, M. Yamamoto, A. Nandi, K.P. Rosenblatt, et al.,
Regulation of fibroblast growth factor-23 signaling by klotho, J. Biol. Chem. 281
(2006) 6120–6123, http://dx.doi.org/10.1074/jbc.C500457200.
[56] Y. Matsumura, H. Aizawa, T. Shiraki-Iida, R. Nagai, M. Kuro-o, Y. Nabeshima, Identification of the human klotho gene and its two transcripts encoding membrane
and secreted klotho protein, Biochem. Biophys. Res. Commun. 242 (1998)
626–630.
[57] I. Urakawa, Y. Yamazaki, T. Shimada, K. Iijima, H. Hasegawa, K. Okawa, et al., Klotho
converts canonical FGF receptor into a specific receptor for FGF23, Nature 444
(2006) 770–774, http://dx.doi.org/10.1038/nature05315.
[58] K. Lindberg, R. Amin, O.W. Moe, M.-C. Hu, R.G. Erben, A. Östman Wernerson, et al.,
The kidney is the principal organ mediating klotho effects, J. Am. Soc. Nephrol. 25
(2014) 2169–2175, http://dx.doi.org/10.1681/ASN.2013111209.
[59] M.-C. Hu, M. Shi, J. Zhang, J. Pastor, T. Nakatani, B. Lanske, et al., Klotho: a novel
phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule, FASEB J. 24 (2010) 3438–3450, http://dx.doi.org/10.1096/fj.10-154765.
[60] Q. Chang, S. Hoefs, A.W. van der Kemp, C.N. Topala, R.J. Bindels, J.G. Hoenderop, The
beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel, Science
310 (2005) 490–493, http://dx.doi.org/10.1126/science.1114245.
[61] S.-K. Cha, B. Ortega, H. Kurosu, K.P. Rosenblatt, M. Kuro-o, C.-L. Huang, Removal of
sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via
binding to galectin-1, Proc. Natl. Acad. Sci. U.S.A. 105 (2008) 9805–9810, http://
dx.doi.org/10.1073/pnas.0803223105.
[62] M.T.F. Wolf, S.-W. An, M. Nie, M.S. Bal, C.-L. Huang, Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms, J. Biol. Chem. 289 (2014)
35849–35857, http://dx.doi.org/10.1074/jbc.M114.616649.
[63] M. Liao, E. Cao, D. Julius, Y. Cheng, Structure of the TRPV1 ion channel determined
by electron cryo-microscopy, Nature 504 (2013) 107–112, http://dx.doi.org/10.
1038/nature12822.
[64] L. Zubcevic, M.A. Herzik, B.C. Chung, Z. Liu, G.C. Lander, S.-Y. Lee, Cryo-electron microscopy structure of the TRPV2 ion channel, Nat. Struct. Mol. Biol. (2016)http://
dx.doi.org/10.1038/nsmb.3159.
[65] K. Saotome, A.K. Singh, M.V. Yelshanskaya, A.I. Sobolevsky, Crystal structure of the
epithelial calcium channel TRPV6, Nature 534 (2016) 506–511, http://dx.doi.org/
10.1038/nature17975.
[66] I. Erler, D. Hirnet, U. Wissenbach, V. Flockerzi, B.A. Niemeyer, Ca2+-selective transient receptor potential V channel architecture and function require a specific ankyrin repeat, J. Biol. Chem. 279 (2004) 34456–34463, http://dx.doi.org/10.1074/
jbc.M404778200.
[67] Q. Chang, E. Gyftogianni, S.F.J. van de Graaf, S. Hoefs, F.A. Weidema, R.J.M. Bindels,
et al., Molecular determinants in TRPV5 channel assembly, J. Biol. Chem. 279
(2004) 54304–54311, http://dx.doi.org/10.1074/jbc.M406222200.
[68] T. de Groot, E.A.E. van der Hagen, S. Verkaart, V.A.M. te Boekhorst, R.J.M. Bindels,
J.G.J. Hoenderop, Role of the transient receptor potential vanilloid 5 (TRPV5) protein N terminus in channel activity, tetramerization, and trafficking, J. Biol. Chem.
286 (2011) 32132–32139, http://dx.doi.org/10.1074/jbc.M111.226878.
[69] C.B. Phelps, R. Gaudet, The role of the N terminus and transmembrane domain of
TRPM8 in channel localization and tetramerization, J. Biol. Chem. 282 (2007)
36474–36480, http://dx.doi.org/10.1074/jbc.M707205200.
[70] M. Arniges, J.M. Fernández-Fernández, N. Albrecht, M. Schaefer, M.A. Valverde,
Human TRPV4 channel splice variants revealed a key role of ankyrin domains in
multimerization and trafficking, J. Biol. Chem. 281 (2006) 1580–1586, http://dx.
doi.org/10.1074/jbc.M511456200.
[71] J. Myeong, M. Kwak, C. Hong, J.-H. Jeon, I. So, Identification of a membranetargeting domain of the transient receptor potential canonical (TRPC)4 channel
unrelated to its formation of a tetrameric structure, J. Biol. Chem. 289 (2014)
34990–35002, http://dx.doi.org/10.1074/jbc.M114.584649.
[72] C.B. Phelps, R.J. Huang, P.V. Lishko, R.R. Wang, R. Gaudet, Structural analyses of the
ankyrin repeat domain of TRPV6 and related TRPV ion channels, Biochemistry 47
(2008) 2476–2484, http://dx.doi.org/10.1021/bi702109w.
[73] D.-J. Shi, S. Ye, X. Cao, R. Zhang, K. Wang, Crystal structure of the N-terminal ankyrin repeat domain of TRPV3 reveals unique conformation of finger 3 loop critical
for channel function, Protein Cell 4 (2013) 942–950, http://dx.doi.org/10.1007/
s13238-013-3091-0.
[74] K.W. Huynh, M.R. Cohen, J. Jiang, A. Samanta, D.T. Lodowski, Z.H. Zhou, et al., Structure of the full-length TRPV2 channel by cryo-EM, Nat. Commun. 7 (2016) 11130,
http://dx.doi.org/10.1038/ncomms11130.
[75] K.W. Huynh, M.R. Cohen, V.Y. Moiseenkova-Bell, Application of amphipols for
structure-functional analysis of TRP channels, J. Membr. Biol. 247 (2014)
843–851, http://dx.doi.org/10.1007/s00232-014-9684-6.
[76] V.S. Korkosh, B.S. Zhorov, D.B. Tikhonov, Analysis of inter-residue contacts reveals
folding stabilizers in P-loops of potassium, sodium, and TRPV channels, Eur.
Biophys. J. 45 (2016) 321–329, http://dx.doi.org/10.1007/s00249-015-1098-6.
[77] G. Owsianik, D. D'hoedt, T. Voets, B. Nilius, Structure-function relationship of the
TRP channel superfamily, Rev. Physiol. Biochem. Pharmacol. 156 (2006) 61–90.
[78] B. Nilius, R. Vennekens, J. Prenen, J.G. Hoenderop, G. Droogmans, R.J. Bindels, The
single pore residue Asp542 determines Ca2 + permeation and Mg2 + block of
the epithelial Ca2+ channel, J. Biol. Chem. 276 (2001) 1020–1025, http://dx.doi.
org/10.1074/jbc.M006184200.
[79] C.H. Munns, M.-K. Chung, Y.E. Sanchez, L.M. Amzel, M.J. Caterina, Role of the outer
pore domain in transient receptor potential vanilloid 1 dynamic permeability to
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
large cations, J. Biol. Chem. 290 (2015) 5707–5724, http://dx.doi.org/10.1074/jbc.
M114.597435.
J. Payandeh, T. Scheuer, N. Zheng, W.A. Catterall, The crystal structure of a voltagegated sodium channel, Nature 475 (2011) 353–358, http://dx.doi.org/10.1038/
nature10238.
E. Cao, M. Liao, Y. Cheng, D. Julius, TRPV1 structures in distinct conformations reveal activation mechanisms, Nature 504 (2013) 113–118, http://dx.doi.org/10.
1038/nature12823.
F. Zhang, S.M. Hanson, A. Jara-Oseguera, D. Krepkiy, C. Bae, L.V. Pearce, et al., Engineering vanilloid-sensitivity into the rat TRPV2 channel, Elife 5 (2016), e11273,
http://dx.doi.org/10.7554/eLife.16409.
J. Teng, S.H. Loukin, A. Anishkin, C. Kung, L596-W733 bond between the start of the
S4–S5 linker and the TRP box stabilizes the closed state of TRPV4 channel, Proc.
Natl. Acad. Sci. U.S.A. 112 (2015) 3386–3391, http://dx.doi.org/10.1073/pnas.
1502366112.
Z. Lin, Q. Chen, M. Lee, X. Cao, J. Zhang, D. Ma, et al., Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome, Am. J. Hum. Genet. 90 (2012)
558–564, http://dx.doi.org/10.1016/j.ajhg.2012.02.006.
S. Duchatelet, L. Guibbal, S. de Veer, S. Fraitag, P. Nitschké, M. Zarhrate, et al., Olmsted syndrome with erythromelalgia caused by recessive transient receptor potential vanilloid 3 mutations, Br. J. Dermatol. 171 (2014) 675–678, http://dx.doi.org/
10.1111/bjd.12951.
L. Gregorio-Teruel, P. Valente, B. Liu, G. Fernández-Ballester, F. Qin, A. FerrerMontiel, The integrity of the TRP domain is pivotal for correct TRPV1 channel
gating, Biophys. J. 109 (2015) 529–541, http://dx.doi.org/10.1016/j.bpj.2015.
06.039.
B. Nilius, F. Mahieu, J. Prenen, A. Janssens, G. Owsianik, R. Vennekens, et al., The
Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5biphosphate, EMBO J. 25 (2006) 467–478, http://dx.doi.org/10.1038/sj.emboj.
7600963.
T. Rohács, B. Thyagarajan, V. Lukacs, Phospholipase C mediated modulation of
TRPV1 channels, Mol. Neurobiol. 37 (2008) 153–163, http://dx.doi.org/10.1007/
s12035-008-8027-y.
R.M. Klein, C.A. Ufret-Vincenty, L. Hua, S.E. Gordon, Determinants of molecular
specificity in phosphoinositide regulation. Phosphatidylinositol (4,5)bisphosphate (PI(4,5)P2) is the endogenous lipid regulating TRPV1, J. Biol.
Chem. 283 (2008) 26208–26216, http://dx.doi.org/10.1074/jbc.M801912200.
T. Rohács, C.M.B. Lopes, I. Michailidis, D.E. Logothetis, PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain, Nat.
Neurosci. 8 (2005) 626–634, http://dx.doi.org/10.1038/nn1451.
T. Rohács, Phosphoinositide regulation of TRP channels, Handb. Exp. Pharmacol.
223 (2014) 1143–1176, http://dx.doi.org/10.1007/978-3-319-05161-1_18.
P. Velisetty, I. Borbiro, M.A. Kasimova, L. Liu, D. Badheka, V. Carnevale, et al., A molecular determinant of phosphoinositide affinity in mammalian TRPV channels, Sci
Rep. 6 (2016) 27652, http://dx.doi.org/10.1038/srep27652.
Y. Gao, E. Cao, D. Julius, Y. Cheng, TRPV1 structures in nanodiscs reveal mechanisms
of ligand and lipid action, Nature 534 (2016) 347–351, http://dx.doi.org/10.1038/
nature17964.
F. Zhang, S. Liu, F. Yang, J. Zheng, K. Wang, Identification of a tetrameric assembly
domain in the C terminus of heat-activated TRPV1 channels, J. Biol. Chem. 286
(2011) 15308–15316, http://dx.doi.org/10.1074/jbc.M111.223941.
N. García-Sanz, A. Fernández-Carvajal, C. Morenilla-Palao, R. Planells-Cases, E.
Fajardo-Sánchez, G. Fernández-Ballester, et al., Identification of a tetramerization
domain in the C terminus of the vanilloid receptor, J. Neurosci. 24 (2004)
5307–5314, http://dx.doi.org/10.1523/JNEUROSCI.0202-04.2004.
T. de Groot, S. Verkaart, Q. Xi, R.J.M. Bindels, J.G.J. Hoenderop, The identification of
Histidine 712 as a critical residue for constitutive TRPV5 internalization, J. Biol.
Chem. 285 (2010) 28481–28487, http://dx.doi.org/10.1074/jbc.M110.117143.
V. Vlachova, J. Teisinger, K. Susankova, A. Lyfenko, R. Ettrich, L. Vyklicky, Functional
role of C-terminal cytoplasmic tail of rat vanilloid receptor 1, J. Neurosci. 23 (2003)
1340–1350.
N. Hellwig, N. Albrecht, C. Harteneck, G. Schultz, M. Schaefer, Homo- and
heteromeric assembly of TRPV channel subunits, J. Cell Sci. 118 (2005) 917–928,
http://dx.doi.org/10.1242/jcs.01675.
B.I. Yeh, Y.K. Kim, W. Jabbar, C.-L. Huang, Conformational changes of pore helix
coupled to gating of TRPV5 by protons, EMBO J. 24 (2005) 3224–3234, http://dx.
doi.org/10.1038/sj.emboj.7600795.
T. de Groot, K. Lee, M. Langeslag, Q. Xi, K. Jalink, R.J.M. Bindels, et al., Parathyroid
hormone activates TRPV5 via PKA-dependent phosphorylation, J. Am. Soc.
Nephrol. 20 (2009) 1693–1704, http://dx.doi.org/10.1681/ASN.2008080873.
D. Gkika, C.N. Topala, Q. Chang, N. Picard, S. Thebault, P. Houillier, et al., Tissue kallikrein stimulates Ca(2+) reabsorption via PKC-dependent plasma membrane accumulation of TRPV5, EMBO J. 25 (2006) 4707–4716, http://dx.doi.org/10.1038/sj.
emboj.7601357.
S.F.J. van de Graaf, J.G.J. Hoenderop, R.J.M. Bindels, Regulation of TRPV5 and TRPV6
by associated proteins, Am. J. Physiol. Renal Physiol. 290 (2006) F1295–F1302,
http://dx.doi.org/10.1152/ajprenal.00443.2005.
S.F.J. van de Graaf, J.G.J. Hoenderop, D. Gkika, D. Lamers, J. Prenen, U. Rescher, et al.,
Functional expression of the epithelial Ca(2+) channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex, EMBO J. 22 (2003)
1478–1487, http://dx.doi.org/10.1093/emboj/cdg162.
M. Palmada, S. Poppendieck, H.M. Embark, S.F.J. van de Graaf, C. Boehmer, R.J.M.
Bindels, et al., Requirement of PDZ domains for the stimulation of the epithelial
Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and
glucocorticoid inducible kinase SGK1, Cell. Physiol. Biochem. 15 (2005) 175–182,
http://dx.doi.org/10.1159/000083650.
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027
M.K.C. van Goor et al. / Biochimica et Biophysica Acta xxx (2016) xxx–xxx
[105] B. Nilius, F. Weidema, J. Prenen, J.G.J. Hoenderop, R. Vennekens, S. Hoefs, et al., The
carboxyl terminus of the epithelial Ca(2+) channel ECaC1 is involved in Ca(2+)dependent inactivation, Pflugers Arch. 445 (2003) 584–588, http://dx.doi.org/10.
1007/s00424-002-0923-9.
[106] B. Holakovska, L. Grycova, J. Bily, J. Teisinger, Characterization of calmodulin binding domains in TRPV2 and TRPV5 C-tails, Amino Acids 40 (2011) 741–748, http://
dx.doi.org/10.1007/s00726-010-0712-2.
[107] T.T. Lambers, A.F. Weidema, B. Nilius, J.G.J. Hoenderop, R.J.M. Bindels, Regulation of the mouse epithelial Ca2(+) channel TRPV6 by the Ca(2 +)-sensor
11
calmodulin, J. Biol. Chem. 279 (2004) 28855–28861, http://dx.doi.org/10.
1074/jbc.M313637200.
[108] L. Grycova, B. Holendova, Z. Lansky, L. Bumba, M. Jirku, K. Bousova, et al., Ca(2+)
binding protein S100A1 competes with calmodulin and PIP2 for binding site on
the C-terminus of the TPRV1 receptor, ACS Chem. Neurosci. 6 (2015) 386–392,
http://dx.doi.org/10.1021/cn500250r.
[109] S.H. Loukin, J. Teng, C. Kung, A channelopathy mechanism revealed by direct calmodulin activation of TrpV4, Proc. Natl. Acad. Sci. U.S.A. 112 (2015) 9400–9405,
http://dx.doi.org/10.1073/pnas.1510602112.
Please cite this article as: M.K.C. van Goor, et al., TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of
TRPV5 and TRPV6, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbamcr.2016.11.027