Cell surface proteoglycans comprise a transmembrane or membrane-associated core protein to which one or more glycosaminoglycan chains are covalently attached. They are ubiquitous receptors on nearly all animal cell surfaces. In mammals, the cell surface proteoglycans include the six glypicans, CD44, NG2 (CSPG4), neuropilin-1 and four syndecans. A single syndecan is present in invertebrates such as nematodes and insects. Uniquely, syndecans are receptors for many classes of proteins that can bind to the heparan sulphate chains present on syndecan core proteins. These range from cytokines, chemokines, growth factors and morphogens to enzymes and extracellular matrix (ECM) glycoproteins and collagens. Extracellular interactions with other receptors, such as some integrins, are mediated by the core protein. This places syndecans at the nexus of many cellular responses to extracellular cues in development, maintenance, repair and disease. The cytoplasmic domains of syndecans, while having no intrinsic kinase activity, can nevertheless signal through binding proteins. All syndecans appear to be connected to the actin cytoskeleton and can therefore contribute to cell adhesion, notably to the ECM and migration. Recent data now suggest that syndecans can regulate stretch-activated ion channels. The structure and function of the syndecans and the ion channels are reviewed here, along with an analysis of ion channel functions in cell–matrix adhesion. This area sheds new light on the syndecans, not least since evidence suggests that this is an evolutionarily conserved relationship that is also potentially important in the progression of some common diseases where syndecans are implicated.

Introduction

Evidence from biochemistry experiments more than 30 years ago suggested that proteoglycans on the cell surface may support cell adhesion [1,2]. This was long before any of the core proteins had been sequenced and even predated the discovery of the integrin receptors. Further work suggested that some heparan sulphate proteoglycan (HSPG) core proteins had hydrophobic properties and could be selectively enriched using hydrophobic chromatography on octyl-agarose or similar matrices [3,4]. Subsequently, two major classes of cell surface, membrane-associated HSPGs were identified, the syndecans and glypicans. Both have a long evolutionary history, being present in invertebrate members of the Bilateria and in vertebrates [57]. In mammals, there are four syndecan and six glypican genes. Accumulating evidence over the past decade has, however, pointed to roles for glypicans in the control of growth factor, morphogen and cytokine responses rather than any direct role in cell–matrix adhesion [8]. This is consistent with the fact that glypican core proteins are connected by a glycosylphosphatidylinositol anchor to the membrane, and hence cannot communicate directly with the cytoskeleton. In contrast, all the syndecan core proteins have a quite conserved short cytoplasmic domain that can interact with the actin cytoskeleton, while not having any intrinsic kinase activity [9]. Therefore, signalling through syndecans relies on the docking of partner proteins, e.g. protein kinase Cα in the case of syndecan-4 [10]. In this review, we shall focus on the syndecans. For the structure and assembly of glycosaminoglycan chains including heparan sulphate (HS), there are several recent comprehensive reviews [1114].

It has also been appreciated for several decades that the cytosolic ionic environment is tightly regulated by a complex system of channels, pumps and exchangers. In this way, membrane potential, intracellular pH, cell volume, signalling through calcium-mediated pathways and some aspects of transcriptional regulation are controlled. With regard to cell adhesion and the actin cytoskeleton, intracellular pH influences cortactin–cofilin interactions [15] and talin–actin interactions [16], while calcium, through several mechanisms, can influence cytoskeletal architecture and contraction [17,18]. Several widespread calcium-binding protein pathways are known, e.g. myosin/myosin light chain kinase, calmodulin (CaM) and CaMkinases, the proteinase calpain, actin-bundling behaviour of some actinin isoforms and the phosphatase calcineurin. The last of these has a major role in the nFAT signalling pathway to transcriptional regulation, but is also a potential regulator of slingshot phosphatase activity and thereby controls cofilin phosphorylation status and function [19]. Calcium signalling is therefore central not only to actin cytoskeleton organization with impact on adhesion and migration, but also signals in growth, differentiation and apoptosis pathways in addition to roles in neuronal and muscle function and calcified skeletal tissue [18,20,21]. Moreover, there is tight regulation of cytosolic calcium concentration regulated by transport into and out of stores, such as the endoplasmic reticulum (ER) and other microdomains within cells. It is noted, for example, that cytosolic calcium levels may form a gradient from front to back of motile cells, while there is also the possibility for minute-to-minute variations driven by pump and channel activities (e.g. flickers/oscillations) that can be localised to microdomains within the cell [22].

In the recent past, experimental work has, unexpectedly, shown a linkage between cell surface proteoglycans of the syndecan family and a subset of ion channels. Given this new concept, we review the roles of proteoglycans and the cytosolic ionic environment in controlling cell–ECM interactions and junction formation.

Syndecan structure

Syndecan proteoglycans have four functional domains (Figure 1). In the extracellular environment is the majority of the core protein to which glycosaminoglycan chains are covalently attached. These are predominantly HS, but some syndecans also possess chondroitin/dermatan sulphate chains [9]. The core protein and the HS chains, in particular, can bind protein ligands. It was originally assumed that HS was the major site of interaction with extracellular matrix (ECM) proteins, and also a plethora with a plethora of growth factors, cytokines, chemokines and enzymes [23]. Many of these have ‘heparin-binding domains’ which in practice allows most to interact with the less sulphated HS encountered in most HSPGs [14]. However, it is now clear that the region of the core protein between the N-terminal HS chains and the transmembrane domain, while not highly conserved in terms of sequence, nevertheless has important interaction capabilities. Some integrins, associated receptors and growth factor receptors can dock, with increasing evidence that signalling through these complexes is partly controlled by the contributing syndecan [2426]. However, what remains unclear is how ligand binding to either the glycosaminoglycan chains or the external core protein promotes intracellular signalling. Probably, there are clustering events that follow ligand binding, but this remains an intriguing challenge for the future.

Schematic of syndecan and the two stretch-activated ion channels that have been focal adhesion-localised, TRPC7 and TRPM4.

Figure 1.
Schematic of syndecan and the two stretch-activated ion channels that have been focal adhesion-localised, TRPC7 and TRPM4.

Their structure and some interactions of the syndecan are indicated. TM: transmembrane domain; C1 and C2: conserved cytoplasmic regions of syndecans; V: variable region of syndecans; A: ankyrin repeats; MHR: TRPM homology repeats.

Figure 1.
Schematic of syndecan and the two stretch-activated ion channels that have been focal adhesion-localised, TRPC7 and TRPM4.

Their structure and some interactions of the syndecan are indicated. TM: transmembrane domain; C1 and C2: conserved cytoplasmic regions of syndecans; V: variable region of syndecans; A: ankyrin repeats; MHR: TRPM homology repeats.

The single transmembrane domains of syndecans are powerful drivers of dimerisation [27,28], and it appears that syndecans may commonly be present as homodimers on the cell surface. There is even evidence for heterodimers, or perhaps heterocomplexes of syndecan dimers [29]. The short cytoplasmic domains of syndecans have, on conservation and functional grounds, been divided into three small regions: C1, V and C2 [9]. The membrane-proximal C1 (conserved) interacts with cytoskeleton and signalling proteins and appears to be a major site for controlling syndecan internalisation. The V (variable) region seems to be responsible for syndecan-specific signalling, in the sense that this region is not conserved between different syndecan core proteins, but is conserved across species. The V region of human syndecan-4 is virtually identical with that of mouse, chicken and zebrafish (e.g. [9]). The C2 (conserved) region has a hydrophobic tail that binds PDZ domain proteins, such as syntenin [9,30,31]. This may be required for assembling syndecans into networks at the cell surface, but may also be important for trafficking and exosome formation [32].

Cell–matrix junctions

Many cells that interact with the ECM form junctions that have varying stability, but can be important in regulating cell migration, survival and growth. In mammalian cells, these are the hemidesmosomes and the focal adhesions (also known as focal contacts, etc). While both are integrin-mediated structures, they are intrinsically very different in composition and function. Integrin β4 is a major transmembrane element of, and required for, hemidesmosome assembly [33,34]. These junctions are linked to the 10 nm filament (intermediate filament) system and provide a strong linkage to the ECM that resists shear forces, typically in epithelia. Rare but devastating genetic blistering diseases are known, particularly in the epidermis, where hemidesmosome formation is compromised [35]. In contrast, focal adhesions are linked to the actin cytoskeleton through mainly β1 or β3 integrins. It has long been appreciated that focal contacts/adhesions can be transient or more long-lasting structures and that their number and size may be inversely proportional to the migration rate [36]. They are certainly sites of mechanosensing and mechanotransduction that can affect cell behaviour [3739].

No proteoglycans, ion pumps, channels or exchangers have been noted in hemidesmosomes. This is perhaps an indicator of their structural role, with limited dynamics. The cytoplasmic domain of integrin β4 has been shown to interact with syndecans-1 and -4, but this may relate to non-junctional roles for the integrin [40]. With regard to focal adhesions, a role for one proteoglycan in particular, syndecan-4, has been noted many times [9,4143]. Using plasma-derived fibronectin as a model substrate, it was shown over 30 years ago that focal adhesion assembly in fibroblasts was strongly promoted by its high-affinity HepII domain [44]. Subsequently, the interaction of this domain with the HS chains of syndecan-4 became clear, but it has taken a considerable time to elucidate the proteoglycan's role in the process. Consistent with the specificity of syndecan-4 in promoting focal adhesion formation, the V region of its cytoplasmic domain was established as key to its role. This region, which has a unique twisted-clamp dimeric structure [27], binds both the lipid phosphatidylinositol 4,5-bisphosphate and also protein kinase Cα [45]. In turn, the kinase can not only phosphorylate many potential substrates, including some cytoskeletal proteins, but also regulators of the Rho superfamily of small G proteins [46]. Examples may include p190 RhoGAP and the dissociation inhibitor RhoGDIα [47,48]. Since Rho and Rac proteins are known, in their GTP-loaded form, to regulate the actin cytoskeleton, this provided one link between the proteoglycan and focal adhesion assembly.

In addition, the syndecan-4 V region can interact with α-actinin (actinin-1). Disturbance of this interaction clearly altered actin stress fibre architecture, and the interaction site was mapped to one of the protein's four spectrin repeats [49]. This actin-bundling protein has also been reported to interact with the cytoplasmic domain of some integrins [50,51], and taken together, this would lead to an expectation that α-actinin may be localised not only in the actin filament bundles, but also close to the membrane at focal adhesions. Super-resolution imaging of adhesions has been reported, but this places α-actinin not only in the membrane-proximal ‘signalling layer’ but also at the interface with the actin cytoskeleton in the ‘force transduction’ layer [52]. Perhaps, direct interactions between α-actinin and syndecan-4 or integrins are ephemeral or depend on the motility status of the cells.

Focal adhesions in the past few years have been prepared and analysed by mass spectrophotometric techniques by several groups. Differing cell types and methods were used in the various studies. This has given rise to an extensive ‘integrin adhesome’ of over 2000 proteins. Remarkably, only 10 proteins figure in all seven analyses, including three integrin subunits: α-actinin-4, vinculin and integrin-linked kinase [53]. However, the list lengthens when, including proteins, found in six of seven analyses, including α-actinin-1, paxillin and focal adhesion kinase (FAK). From all these data, a core adhesome of 60 proteins has been identified, which is dominated by integrin subunits along with structural, actin-associated or adaptor proteins [53]. Listed in the literature are five channel proteins, reported as focal adhesion-associated, but none has been identified by proteomic analysis. These are SLC9A1 (NHE1, a sodium-proton exchanger), SLC16A3 [MCT4, a monocarboxylate transporter that forms a complex with CD147 (emmprin/basigin)], PKD1 [polycystin-1, TRP polycystin (TRPP1)], KCNH2 (Kv11.1, hERG1, a voltage-gated potassium channel) and TRP melastatin 7 (TRPM7; a transient receptor potential channel — see below). However, it may be that these channels are not either uniformly localised with focal adhesions or are highly cell type-restricted. In each case, however, evidence has been presented that shows an association with integrin. For example, Cherubini et al. [54] show that KCNH2 associates with β-integrin, but at least in HEK cells does not exhibit focal adhesion localisation. NHE1 is similarly known to have integrin association, but, while present towards the leading edges of cells, does not have a distribution pattern resembling focal adhesions [55,56]. Moreover, recent data suggest that this exchanger links to the ezrin/radixin/moesin proteins (that are not considered as focal adhesion components) and may have a key role in the invadopodia of tumour cells [57]. Local alkalinisation resulting from channel opening can disrupt cortactin–cofilin interactions, with subsequent actin–cofilin-driven formation of the invadopodia structure. Invadopodia are organelles of both adhesion and ECM degradation, being enriched in integrin but also metalloproteinases such as MMP14 (MT1-MMP; [58]). They are therefore not identical in form or function with focal adhesions, but are nevertheless important in tumour cell invasion and metastasis [59,60]. TRPM7, another invadopodium component, clearly affects actomyosin organisation and promotes podosome and invadopodia formation. Its suppression, on the other hand, can lead to an altered balance of adhesion organelles favouring focal adhesion formation, but not in all cell types [61,62].

While not necessarily being a focal adhesion component, NHE1 expression can be enriched at the leading edges of cells where its activity can lead to distinct pH nanodomains in the vicinity of focal adhesions. These favour turnover, so that, in its absence, focal adhesions can be stabilised [56]. It seems doubtful that SLC16A3 (MCT4) and PKD1 (polycystin-1, TRPP1) are genuine focal adhesion components based on an examination of their localisation, although associating with integrin, perhaps indirectly [63]. Moreover, when SLC16A3 (MCT4) or PKD-1 is suppressed, this leads to enhanced focal adhesion assembly [64,65]. In the case of PKD1, there are suggestions that the protein instead associates with 10 nm filaments and desmosomes [66,67].

Are any channels genuine focal adhesion components?

Although there has been a lack of proteomic data suggesting that channel proteins can be focal adhesion components, it has to be borne in mind that they may be present at very low concentration and may be difficult to prepare in quantity given that many have multiple membrane-spanning domains. However, deHart et al. [68] presented clear data that a specific integrin, α9β1, when present in focal adhesions of fibroblasts seeded on a tenascin-C domain substrate, co-localised with the inward rectifier channel Kir4.2. Moreover, knockdown of the channel slowed migration and enhanced lamellipodia formation, indicative of an impact on the actin cytoskeleton [68].

In the past 18 months, a link between syndecan-4 and the TRPC7 (transient receptor potential canonical 7) calcium channel has been demonstrated. Moreover, the latter was seen to be a focal adhesion component, consistent with syndecan-4's role (Figures 1 and 2). The channel had a distribution resembling that of α-actinin-1, and a complex of this protein, syndecan-4 and the channel could be immunoprecipitated [69]. Interactions between TRPC6 (a close homologue of TRPC7) and α-actinin-1 have been recorded [70]. Moreover, α-actinin appears to interact with many channels at the cell surface [7173]. It had been known for some time that fibroblasts lacking syndecan-4 had a compromised cytoskeletal organisation, with reduced focal adhesion size and abundance commensurate with fewer stress fibres. This phenotype could be ‘corrected’ by re-expression of the syndecan, but now it could also be shown that suppression of the TRPC7 channel by siRNA would have the same effect. Analysis showed elevated cytosolic calcium levels in the knockout fibroblasts that reduced to wild-type levels either by replenishing syndecan-4 or removing the TRPC7. In summary, it appeared that the syndecan-4 null cytoskeletal phenotype in the fibroblasts was entirely due to the altered activity of the calcium channel [69]. Further work suggested that protein kinase C could signal reductions in cytosolic calcium, so it may be that the syndecan-4–PKC signalling axis controls multiple components of the cytoskeletal response to the ECM.

Ion channels as focal adhesion components.

Figure 2.
Ion channels as focal adhesion components.

Triple staining for TRPC7 (green), TRPM4 (red) and F-actin (blue) in primary rat embryo fibroblasts. Typical focal adhesion patterns are seen by immunocytochemistry for the two channels. The large panel shows the three-channel overlay, whereas individual channels are shown on the right. F-actin was stained with phalloidin. Scale bar = 10 µm.

Figure 2.
Ion channels as focal adhesion components.

Triple staining for TRPC7 (green), TRPM4 (red) and F-actin (blue) in primary rat embryo fibroblasts. Typical focal adhesion patterns are seen by immunocytochemistry for the two channels. The large panel shows the three-channel overlay, whereas individual channels are shown on the right. F-actin was stained with phalloidin. Scale bar = 10 µm.

Further work in this same study showed that syndecan-1, though not a focal adhesion component, could regulate another channel, TRPC4. Moreover, this property appears to be an ancient one, since genetic experiments in Caenorhabditis elegans also pointed to a syndecan–transient receptor potential (TRP) channel association [69].

A short time later, another paper appeared showing that a different channel, TRPM4, was also a focal adhesion component and that it had an important role in the control of cell migration [74]. Figure 2 shows fibroblasts stained for TRPM4 and TRPC7, both of which have the characteristic linear streaks of focal adhesions. TRPM4 is a calcium-activated monovalent ion channel, but whether the two channels interact with heteromers is not known. Moreover, these channels can be expressed in several alternately spliced isoforms, and it is not yet clear whether one or more specific isoforms are focal adhesion-localised, as has been shown previously for the phosphatidylinositol-4-phosphate 5-kinase [75]. Given these recent developments, further details on the TRP channels are provided below.

TRP protein structure and functions

Each TRP subfamily has distinct functions and mode of regulation [76]. Despite the functional differences, five closely related TRP subfamilies can be considered as one group, known as Group-1 channels [77,78]. Members of this group are TRPC, TRP vanilloid, TRPM, TRP ankyrin and TRPN [79]. Another TRP group is Group-2 TRPs, which has two subfamilies: TRP mucolipin and TRPPs. Low homology is observed between the Group-1 and Group-2 TRPs [80].

Significant structural similarity is identified between TRPs since all of them contain six transmembrane domains with intracellular N- and C-termini and a pore region that is located between the fifth and sixth transmembrane domain. In addition, except for TRPMs, they have three or more ankyrin repeats in the N-terminus which have roles in protein–protein interactions including the formation of homomers or hetromers of TRP proteins [8183]. Some TRPMs also differ by containing a C-terminal kinase domain. TRPC, TRPM and TRPN channels have a conserved TRP motif C-terminal of the sixth transmembrane domain that can form an amphipathic helix important for protein interactions and gating function [84,85]. The result of homomeric and heteromeric interactions between TRP proteins that belong in the same subfamily is the formation of TRP channels. TRP channels are expressed almost universally, in organisms from fungi to mammals. The TRP channels expressed in yeast and fungi are known as TRPY (yeast). TRPs are gated by physical and chemical stimuli, including stretch, changes in temperature, touch, light, pH and endogenous or exogenous ligands [8688]. Little is known about the molecular mechanisms underlying TRP channel stimulus detection and regulation of channel opening. The pore helix of TRP channels plays a conserved role in gating [89].

The TRPC subfamily (Table 1 and Figure 3) consists of seven members (six in human; TRPC2 is a pseudogene) that may be divided in four subsets based on their functional similarities and amino acid homology: TRPC1, TRPC2, TRPC3/6/7 (∼80% homology) and TRPC4/5 (∼60% homology). TRPC subunits can be combined forming functional homo- and heterotetrameric ion channels. TRPC1, for example, may form heteromeric complexes with TRPC3 and TRPC4/5. TRPC3/-6 and -7 form heterotetramers with different properties from homotetramers. TRPC4/5 may form homo- or heterotetramers via their NH2-terminal ankyrin repeats [83]. The majority of studies report the effects of exogenously expressed TRPC in cellular processes, whereas the endogenous protein regulation and function is not completely understood. It is shown that the TRPC subfamily is involved in Ca2+ entry mechanisms since depletion of internal Ca2+ stores triggers the channel gate opening as with all store-operated channels (SOCs) [88].

Schematics of TRPC channels summarising some aspects of their regulation.

Figure 3.
Schematics of TRPC channels summarising some aspects of their regulation.

A: ankyrin repeats; N, C: N- and C-termini of the channel proteins; PLC: phospholipase C; DAG: diacylglycerol; InsP3: inositol trisphosphate; PtdIns4,5P2: phosphatidylinositol 4,5 bisphosphate; TRP domain: pore regulatory motif.

Figure 3.
Schematics of TRPC channels summarising some aspects of their regulation.

A: ankyrin repeats; N, C: N- and C-termini of the channel proteins; PLC: phospholipase C; DAG: diacylglycerol; InsP3: inositol trisphosphate; PtdIns4,5P2: phosphatidylinositol 4,5 bisphosphate; TRP domain: pore regulatory motif.

Table 1
Properties of TRPC and TRPM subfamily members
Channel Gating Permeability Highest expression in Homology Ref. 
TRPC subfamily 
TRPC1 Store depletion, InsP3 Non-selective cation Heart, brain, testis, liver, spleen – [76,82,83,89
TRPC2 DAG Non-selective cation Pseudogene in humans, testis – [76,83,89
TRPC3 DAG, InsP3R, PKC Non-selective cation Brain TRPC6, TRPC7 [76,83,89,120
TRPC4 Gq/11 family GPCRs, InsP3 Non-selective cation Brain, endothelia, adrenal gland, retina, testis TRPC5 [76,83,89,118,119
TRPC5 Gq/11 family GPCRs, InsP3 Non-selective cation Brain TRPC4 [76,83,89
TRPC6 DAG, InsP3 Non-selective cation Lung, brain, ovary TRPC3, TRPC7 [76,83,89
TRPC7 DAG, PKC Non-selective cation Eye, heart, lung TRPC3, TRPC6 [76,83,89,120
TRPM subfamily 
TRPM1 Constitutively open Non-selective cation Melanosomes, brain TRPM3 [76,8993
TRPM2 ADP-ribose, NAD+, H2O2 Non-selective (Na+, K+, Cs+ and Ca2+Brain, bone marrow, spleen TRPM8 [76,89,90,94,95
TRPM3 Constitutively open Non-selective (Na+, K and Ca) Kidney, brain TRPM1 [76,89,90,96
TRPM4 [Ca2+]i, voltage-modulated, PtdIns4,5P2 Monovalent cation selective (Na+, K+ and Cs+Heart, liver, prostate, colon, testis TRPM5 [76,89,90
TRPM5 [Ca2+]i, voltage-modulated, PtdIns4,5P2 Monovalent cation selective (Na+, K+ and Cs+Intestine, liver, lung TRPM4 [76,83,89,90,128
TRPM6 Constitutively open, Mg2+-inhibited Divalent cation selective (Ca2+ and Mg2+Kidney, small intestine TRPM7 [76,89,90
TRPM7 Mg2+-inhibited, ATP, phosphorylation, PtdIns4,5P2, PKC Divalent cation selective (Ca2+, Mg2+, Zn2+ and Ni2+Kidney, heart, bone, adipose TRPM6 [76,89,90,112
TRPM8 Cold, methanol, PtdIns4,5P2 Non-selective (Na+, K+, Cs+ and Ca2+Prostate, liver TRPM2 [76,89,90,100
Channel Gating Permeability Highest expression in Homology Ref. 
TRPC subfamily 
TRPC1 Store depletion, InsP3 Non-selective cation Heart, brain, testis, liver, spleen – [76,82,83,89
TRPC2 DAG Non-selective cation Pseudogene in humans, testis – [76,83,89
TRPC3 DAG, InsP3R, PKC Non-selective cation Brain TRPC6, TRPC7 [76,83,89,120
TRPC4 Gq/11 family GPCRs, InsP3 Non-selective cation Brain, endothelia, adrenal gland, retina, testis TRPC5 [76,83,89,118,119
TRPC5 Gq/11 family GPCRs, InsP3 Non-selective cation Brain TRPC4 [76,83,89
TRPC6 DAG, InsP3 Non-selective cation Lung, brain, ovary TRPC3, TRPC7 [76,83,89
TRPC7 DAG, PKC Non-selective cation Eye, heart, lung TRPC3, TRPC6 [76,83,89,120
TRPM subfamily 
TRPM1 Constitutively open Non-selective cation Melanosomes, brain TRPM3 [76,8993
TRPM2 ADP-ribose, NAD+, H2O2 Non-selective (Na+, K+, Cs+ and Ca2+Brain, bone marrow, spleen TRPM8 [76,89,90,94,95
TRPM3 Constitutively open Non-selective (Na+, K and Ca) Kidney, brain TRPM1 [76,89,90,96
TRPM4 [Ca2+]i, voltage-modulated, PtdIns4,5P2 Monovalent cation selective (Na+, K+ and Cs+Heart, liver, prostate, colon, testis TRPM5 [76,89,90
TRPM5 [Ca2+]i, voltage-modulated, PtdIns4,5P2 Monovalent cation selective (Na+, K+ and Cs+Intestine, liver, lung TRPM4 [76,83,89,90,128
TRPM6 Constitutively open, Mg2+-inhibited Divalent cation selective (Ca2+ and Mg2+Kidney, small intestine TRPM7 [76,89,90
TRPM7 Mg2+-inhibited, ATP, phosphorylation, PtdIns4,5P2, PKC Divalent cation selective (Ca2+, Mg2+, Zn2+ and Ni2+Kidney, heart, bone, adipose TRPM6 [76,89,90,112
TRPM8 Cold, methanol, PtdIns4,5P2 Non-selective (Na+, K+, Cs+ and Ca2+Prostate, liver TRPM2 [76,89,90,100

The TRPM subfamily (Table 1 and Figure 4) has eight members divided into four main groups according to their sequence homology: TRPM1/3, TRPM2/8, TRPM4/5 and TRPM6/7 [90]. The putative pore-forming region of TRPM channels may be located in the loop between transmembrane 5 (TM5) and TM6, similar to other TRP channels. TRPM channels exhibit differences in Ca2+ permeability. TRPM3, TRPM2 and TRPM8 exhibit low Ca2+ permeability, and TRPM6 and TRPM7 channels are non-selective cation channels that exhibit high Ca2+ and Mg2+ permeability [90]. TRPM4 and TRPM5 are Ca2+ impermeable, but are activated by micromolar concentrations of intracellular Ca2+ [83].

Schematics of TRPM channels, with some mechanisms of their regulation shown.

Figure 4.
Schematics of TRPM channels, with some mechanisms of their regulation shown.

ADPR: adenosine diphosphate-ribose; MHR: TRPM homology repeats; N, C: N- and C-termini of the channel proteins; PtdIns4,5P2: phosphatidylinositol 4,5-bisphosphate; TRP domain: pore regulatory motif.

Figure 4.
Schematics of TRPM channels, with some mechanisms of their regulation shown.

ADPR: adenosine diphosphate-ribose; MHR: TRPM homology repeats; N, C: N- and C-termini of the channel proteins; PtdIns4,5P2: phosphatidylinositol 4,5-bisphosphate; TRP domain: pore regulatory motif.

TRPM1 is a prognostic marker for metastasis in malignant melanoma [9193]. The existence of different splice variants of TRPM1 has complicated the investigation of its function. However, it seems that TRPM1 is a constitutively open, non-selective cation channel. TRPM2 is a non-selective cation channel with a characteristic enzymatic ADP-ribose pyrophosphatase domain in the cytoplasmic C-terminal tail of the channel with commensurate ADP-ribose activation of the channel [94,95]. TRPM3 is tissue-restricted and is present in the human kidney and the brain [90]. Since it is permeable to Ca2+ and activated by hypotonicity, TRPM3 may be involved in renal Ca2+ homeostasis [96]. TRPM4 and TRPM5 are ubiquitously expressed Ca2+ -activated monovalent selective cation channels. Both of them are permeable to Na+ and K+ but impermeable to Ca2+. Three isoforms of TRPM4 have been shown in human. TRPM4b is the full-length human clone that encodes a functional channel. TRPM4a is a splice variant that lacks 174 amino acid residues at the N-terminus [97]. Studies of TRPM4a and TRPM4b have shown that differences in the N-termini of the isoforms seem to be essential for their cellular localisation and function. TRPM4a may be located in cytosolic compartments, and though it may be non-functional, it can negatively regulate TRPM4b by influencing Ca2+ mobilisation [98]. Another splice variant, TRPM4c, lacks 537 N-terminal amino acids and its function has not yet been investigated [97]. It is not known which isoform is present in focal adhesions. TRPM6 and TRPM7 possess C-terminal kinase activity that autophosphorylates TRPM7 and phosphorylates annexin-1 [99]. TRPM8 expression is associated with prostate cancer and is an androgen-responsive channel. It is a cold- and menthol-activated non-selective channel [100].

Regulation of TRPC and TRPM channels in cell adhesion and migration

Migration requires turnover of cell – ECM adhesion complexes with continuous cytoskeleton rearrangement and alterations of cell shape. Ion channels and transporters, which are located at FAs, may play their part by regulating intracellular ion concentrations and forming macromolecular complexes with cell adhesion molecules and other signalling proteins [101]. Focal adhesion stability shows a biphasic pH-dependence since alterations in extracellular or pericellular pH values affect focal adhesion dynamics [102] and α2β1 integrin-mediated melanoma cell migration (e.g. [103]). Acidic extracellular pH promotes the opening of the αvβ3 integrin headpiece, revealing an ion-sensitive integrin activation mechanism [104]. Moreover, the glycocalyx, of which proteoglycans are a prominent component, has been shown to play a key role in stabilising extracellular pH, presumably through its charge and ion exchange characteristics [105].

Multiple Ca2+ channels are associated with cancer cell migration and metastasis. Carcinoma metastasis can involve loss of cell–cell junctions and increased cell motility through an epithelial–mesenchymal transition (EMT) process. Associated with this are alterations in interactions with ECM that include MMP-mediated cleavage [106,107]. TRPC6 and probably TRPC1 have been previously shown as regulators of EMT [108,109]. Furthermore, it has been illustrated that suppression of TRPM4 can lead to fibroblastic phenotype of epithelial cells [110]. Voltage-gated Ca2+ channels are co-localised with β1-integrins and seem to be involved in migration [111]. High levels of TRPM7 expression are associated with breast and ovarian cancer progression, whereas TRPM7 silencing inhibits cell proliferation migration, colony formation and invasion followed by an increase in focal adhesion number in various cancer cell lines [112]. TRPC6 is also essential for the development of aggressive glioma phenotype and its silencing inhibits glioma invasion and angiogenesis [113]. The expression of TRPC6, at least in renal tissue, has been shown to be regulated by syndecan-4, both at the mRNA and protein level [114], although the molecular basis for this transcriptional control is not yet understood.

The sources of Ca2+ for signalling could be either internal stores such as the ER or influx from the external environment in response to stimuli such as membrane depolarisation, stretch, extracellular agonists, intracellular messengers or the depletion of internal stores. Several TRPC proteins may be SOC components, whereas all mammalian TRPC channels can be activated by phospholipase C (PLC) [76,80,115]. TRPC4 and TRPC5 are non-selective cation channels that are activated by Gq/11 family GPCRs and PLC enzymatic activity in an InsP3- and diacylglycerol (DAG)-independent pathway [116,117]. The closely related TRPC3, TRPC6 and TRPC7 appear to act independently of internal Ca2+ store depletion and may be activated by DAG. TRPC3 interacts directly with InsP3R and CaM through a CaM/IP3 receptor-binding region. Ca2+-dependent PKC activity mediates inhibition of TRPC3 or TRPC7 by phosphorylation on Ser712 or Ser714, respectively [118]. In this regard, the ability of syndecan-4 cytoplasmic domain to activate PKCα in the presence of PtdIns4,5P2 is potentially relevant [50]. As a conventional isoform, PKCα is Ca2+-dependent for translocation to the membrane [119,120]. However, PtdInsP2 can interact with the beta 3–4 strands of the PKCα C2 domain and potentiate both Ca2+-dependent membrane translocation and kinase activity, as shown by in vitro kinase experiments involving the syndecan-4 cytoplasmic domain [50,119,120]. In addition, TRPC7 is involved in Ca2+ release from stores by its presence in ER membrane and its capacity to suppress the InsP3R activity. TRPC7 may also form heteromers with store-operated and receptor-operated channels in the HEK cell line [121,122].

Of the TRPM channels, TRPM4b may be involved in SOCs by inducing changes in membrane potential, and thus, Ca2+ entry can be enhanced or abolished. Activation of TRPM4b leads to a depolarisation of membrane potential, which promotes the opening of voltage-gated K+ channels and also stops further Ca2+ entry [123]. On the other hand, an increase in Ca2+ influx is observed due to TRPM4b-induced repolarisation of membrane potential. TRPM4b also interacts with TRPC3 forming heteromers in the plasma membrane, suppressing SOC in HEK293T cells. The six TM domains of TRPM4b play a crucial role in protein–protein interactions with TRPC3, suggesting that this may apply to TRPM4a and TRPM4c, since the three isoforms share a similar six transmembrane domain structure. TRPC6 and TRPC7 are highly homologous to TRPC3, perhaps an indication of similar interactions between these TRPC channels and TRPM4 [124]. Mechanical stimulation of TRPC6 triggers activation of TRPM4 and increased [Ca2+]i via activation of voltage-dependent [Ca2+]i channels in smooth muscle cells [125]. Cytoplasmic ATP seems to modulate TRPM4 sensitivity to [Ca2+]i by reversing sensitivity after desensitisation. In addition, CaM-binding and PtdIns4,5P2 increase the [Ca2+]i sensitivity of TRPM4 [126,127]. In contrast, the PtdIns4,5P2 action is associated with positively charged amino acids in a C-terminal pleckstrin homology (PH) domain of TRPM4. The C-terminus of the channel protein contains two PH domains of which the first seems to have a major role. PtdIns4,5P2 dependence is not shown only by TRPM4; other TRPM channels such as TRPM8, TRPM7 and TRPM5 are reported similarly. Mutations of three positive charges in the conserved TRP box and TRP domain of TRPM8 affect the efficiency of PtdIns4,5P2-mediated channel activation [128]. A recent study provides evidence for the key role of sarcoplasmic reticulum Ca2+ release and IP3R2 in the activation of the TRPM4 current. TRPM4 co-localises with IP3R2 at the periphery of atrial myocytes and shear stress indirectly activates the monovalent cation current carried by TRPM4 channels via IP3R2 receptor-mediated Ca2+ release in subsarcolemmal domains of the myocytes [129].

Human TRPM4 contains approximately 130 serine and threonine and 27 tyrosine residues that can be considered as possible phosphorylation targets by different kinases. PKC phosphorylation sites are located on TRPM4 cytoplasmic C-terminus, suggesting a role for PKC in Ca2+-dependent activation [126]. Furthermore, phosphorylation at serine 839 by casein kinase 1 affects the basolateral localisation of TRPM4 in epithelia [130].

TRP channel functions at focal adhesions

The observation of TRP channels at cell–ECM junctions is very new, so their roles remain largely speculative. TRPM4 regulates dendritic and mast cell migration [131,132]. In addition, it now appears to be a focal adhesion regulator [74]. A series of pharmacological inhibition experiments with 9-phenanthrol or shRNA-based knockdown of TRPM4 reveal control of the number, size and turnover of focal adhesions and lamellipodia formation. A possible mechanism is that TRPM4 at focal adhesions causes fast membrane depolarisation that in turn leads to an increase in [Ca2+]i, an important aspect of focal adhesion and cytoskeletal dynamic regulation. In addition, TRPM4 is involved in FAK and Rac GTPase activation, which regulate actin cytoskeleton reorganisation and lamellipodia formation, necessary for cell spreading and migration [74].

Concurrently, TRPC7-mediated calcium influx could readily lead to TRPM4 activation, since they are closely localised and may even interact. However, it is clear that when TRPC7 is depleted by siRNA, focal adhesions still form and indeed are large with substantial associated stress fibres [69]. Therefore, it seems possible that TRPC7 is engaged in focal adhesion turnover, and a necessary future study would seem to be an examination of TRP channels in focal adhesion dynamics. Our preliminary data suggest that neither channel is dependent on the other for focal adhesion localisation, suggesting that their stability and possibly their roles are autonomous.

Membrane tension can be a direct activator of some TRP channels [133,134]. Several TRPC channels, including TRPC1, are localised in caveolar membranes and their expression is caveolin-1-dependent. Caveolae are associated with vesicular transport, transduction mechanisms and signalling pathways [135,136]. Caveolae association with cell shape and actin-controlled changes in membrane tension by caveolae–stress fibre interactions have been recently reviewed [137]. Caveolin-1 and caveolae regulate RhoA-driven actomyosin contractility, which is required for maturation of focal adhesions [138]. Therefore, the connection between TRPC channel activity and FA regulation might result from interactions between caveolae and stress fibres.

There is some evidence for TRPM4 mechanosensitive properties. TRPM4 activation through membrane stretch occurs in rat cerebral artery myocytes, possibly through ryanodine receptor activation, and hTRPM4 overexpressed in HEK293 cells exhibited mechanosensitivity in cell-attached patches. However, TRPM4 seems to possess no inherently mechanosensitive properties when inserted into liposomes, where it forms a functional tetrameric ion channel, but cannot be activated by stretching the lipid bilayer alone. TRPM4 may therefore exhibit mechanosensitivity through additional cytoskeletal components, ECM or other membrane proteins [139].

Another dimension in adhesion dynamics is proteolysis. TRPM7 overexpression or silencing promotes cell spreading and decreased adhesion, and results in the formation of focal adhesions. TRPM7 has been reported as a regulator of calcium-dependent protease m-calpain, which controls cell adhesion through focal adhesion disassembly. TRPM7 may be co-localised with m-calpain at vinculin-containing adhesion complexes [140]. Furthermore, localisation of TRPM7 in podosome or invadosome ring structure in neuroblastoma cells seems to regulate actomyosin contractility through both a kinase-dependent and -independent mechanism [141]. TRPM7 autophosphorylation, triggered by PLC, leads to Ca2+-dependent association of the channel with myosin IIA and consequently phosphorylation of the myosin IIA heavy chain that influences cell adhesion [142]. On the other hand, TRPM7 silencing enhances the phosphorylation of the myosin light chain in vascular endothelial cells [143].

Conclusions

The ability of cell surface syndecans to regulate cell adhesion has a new dimension, now that their interaction with, and regulation of, TRPC channels has been identified [69]. This may open up new possibilities for targeting in disease, but, more immediately, there needs to be further analysis of how this relationship is controlled. Syndecan-4 and its relationship to focal adhesions have proved to be a very amenable system for elucidating functions at the molecular level, but probably all syndecans have analogous roles yet to be determined. Moreover, since the syndecan–TRP channel axis can be demonstrated in invertebrate model organisms, there is also much scope for further genetic experimentation. Syndecans have been implicated in many common diseases ranging from cancers to heart disease and fibrosis, so that understanding their roles in disease progression now may have a new angle to explore.

Abbreviations

     
  • C1 and C2

    conserved regions

  •  
  • CaM

    calmodulin

  •  
  • CSPG4

    chondroitin sulphate proteoglycan 4

  •  
  • DAG

    diacylglycerol

  •  
  • ECM

    extracellular matrix

  •  
  • EMT

    epithelial–mesenchymal transition

  •  
  • ER

    endoplasmic reticulum

  •  
  • FAK

    focal adhesion kinase

  •  
  • HEK

    human embryonic kidney cells 293

  •  
  • hERG1

    human ether a go-go-related gene 1

  •  
  • HS

    heparan sulphate

  •  
  • HSPG

    heparan sulphate proteoglycan

  •  
  • hTRPM4

    human transient receptor potential cation channel subfamily M

  •  
  • InsP3

    inositol 1,4,5-triphosphate

  •  
  • KCNH2

    potassium voltage-gated channel subfamily H member 2

  •  
  • MCT4

    a monocarboxylate transporter

  •  
  • MMP

    matrix metalloproteinase

  •  
  • nFAT

    nuclear factor of activated T-cells

  •  
  • NG2

    neuro/glial antigen 2

  •  
  • NHE1

    a sodium-proton exchanger

  •  
  • PH

    pleckstrin homology

  •  
  • PKC

    protein kinase

  •  
  • CPKD1

    polycystin 1

  •  
  • PLC

    phospholipase C

  •  
  • PtdInsP2

    phosphatidylinositol biphosphate

  •  
  • Rac

    small signalling G protein

  •  
  • RhoGAP

    Rho GTPase activating protein

  •  
  • RhoGDIα

    Rho-GDP-dissociation inhibitor alpha

  •  
  • SLC9A1

    solute carrier family 9 member A1

  •  
  • SOCs

    store-operated channels

  •  
  • TM

    transmembrane

  •  
  • TRPC

    transient receptor potential

  •  
  • TRPC7

    transient receptor potential canonical 7

  •  
  • TRPM

    TRP melastatin

  •  
  • TRPN

    transient receptor ‘no mechanoreceptor potential C’

  •  
  • TRPP1

    TRP polycystin

  •  
  • V

    variable

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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