Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TRPM4

  • Romain Guinamard
  • Christophe Simard
  • Laurent Sallé
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101882

Synonyms

Historical Background

Transient receptor potential, subfamily M(melastatin-related), member 4 (TRPM4) gene encodes a channel protein responsible for a Ca2+-activated nonselective cationic (NSCCa) current. Electrophysiological signatures of such currents are known since the beginning of patch clamp single-channel recordings. They were observed in a wide variety of tissues in the 1980s to 2000s, including epithelia, secretory tissues, or excitable cells (neurons and myocytes) (see Guinamard et al. 2011 for review). However, these currents remained orphaned until the cloning of the TRP gene family at the end of the 1990s. Among these, TRPM1 (melastatin) has been cloned in 1998 and opened the way for the new subfamily TRPM which is composed of eight members (1–8). Based on homology sequence screening of a cDNA library, Xu et al. identified a first sequence of the TRPM4 gene in human (Xu et al. 2001) encoding for a 1040 amino acid protein. Later, a longer splice variant (1214 amino acids) has been cloned (Launay et al. 2002) followed by a shorter one (677 amino acids) (Nilius et al. 2003). These splice variants are successively designated as TRPM4a, TRPM4b, and TRPM4c. However, while TRPM4b protein appeared later as the molecular determinant of most of the NSCCa currents, the physiological significance of TRPM4a and TRPM4c are still in debate. According to this, TRPM4 will be used in the following sections to refer to the full-length protein TRPM4b.

Identification of the TRPM4 protein provided the opportunity to unravel the physiological and pathological implications of the TRPM4 channel. Generation of Trpm4 null mice or RNA interference (iRNA) gave the opportunity to reveal the effect of gene disruption (Barbet et al. 2008; Vennekens et al. 2007). This was concomitant with the description of TRPM4 inhibitors (Ullrich et al. 2005; Grand et al. 2008). In addition, the discovery of TRPM4 mutations associated with cardiac dysfunctions revealed its implication in human physiology and physiopathology (Kruse et al. 2009; Guinamard et al. 2015 for review). These contemporary studies conducted in the 2010s provided a portrait of the roles of TRPM4 in a large variety of processes such as immune response, insulin secretion, smooth muscle activity, onset of respiratory activity, cardiac electrical and mechanical activity, cell differentiation or migration, and ischemia or stroke-induced central nervous system damages.

TRPM4 Structure and Expression Profile

In human, TRPM4 is a gene composed of 25 exons, spanning 54 kb and located in chromosome 19 (Launay et al. 2002). It is a 31 kb spanning gene located in chromosome 7 in mice. It encodes for a protein subunit which holds six transmembrane (TM) domains and intracellular N and C termini (Fig. 1) which is a common architecture with other TRP members. Specific domains were identified along the protein which relate with the regulatory properties of the ion channel: (a) several putative phosphorylation sites for PKA and PKC, (b) four calmodulin-binding sites in the N and C termini, (c) four ATP-binding sites with walker B sequence in the N-terminus and intracellular loop between TM2 and TM3, (d) arginine- and lysine-rich stretches as putative PIP2-binding sites, (e) two ATP-binding cassettes (ABC) transporter-like motifs known to interact with nucleotide-binding domains (NBD) in ABC proteins, and (f) a coiled coil domain in the C-terminus (for reviews, see Mathar et al. 2014; Guinamard et al. 2011). The selectivity filter has been identified in the P loop linking TM5 and TM6. A glycosylation site has also been reported in this P loop. As expected and similarly to a large variety of ion channel proteins, TRPM4 functional channel is composed of a homotetramer. This has been recently demonstrated by electron microscopy after purification of a heterologously expressed TRPM4 protein (Constantine et al. 2016).
TRPM4, Fig. 1

TRPM4 molecular determinants. Topology of the TRPM4 channel. Blue line indicates the polypeptide with the intracellular N- and C-terminal regions and six transmembrane (TM) segments (1–6). Specific regulatory sites are indicated: calmodulin-binding sites (green triangles), PKC sites (yellow diamonds), PIP2-binding site (green square), ABC motifs (blue hexagons), and Walker B ATP-binding sites (red circles). The pore region between TM5 and TM6 holds the selectivity filter and exhibits a glycosylation site. Major mutations reported to be associated with genetic cardiac diseases (conduction blocks or Brugada syndrome) are indicated by circles with the corresponding amino acids and location

TRPM4 mRNA has been detected widely among tissues. In human, it has been reported at high expression level in the heart, pancreas, placenta, and prostate but at a lower level in the kidney, skeletal muscles, liver, intestine, thymus, and spleen (Launay et al. 2002; Nilius et al. 2003). It has also been detected in hematopoietic cell lines including T and B lymphocytes (Launay et al. 2002). At the protein level, TRPM4 is actually considered as mostly expressed at the plasma membrane rather than membranes from organelles. Note that glycosylation of TRPM4 is necessary to stabilize channel expression at the plasma membrane. In addition, phosphorylation influences basolateral targeting in epithelial cells.

TRPM4 Current Properties and Pharmacology

Since TRPM4 is an ion channel, its physiological relevance derives from its ionic current properties. TRPM4 is permeable to monovalent cations, mainly Na+ and K+ that it does not differentiate. By contrast, it is not permeable to Ca2+, unlike most of other TRP channels (Launay et al. 2002, Nilius et al. 2003). Permeability sequence is thus Na+ = K+ > Cs+ > Li+ >> Ca2+. In symmetrical ionic conditions, the single-channel current exhibits a linear current-voltage relationship with a conductance of 20–25 pS (Launay et al. 2002; Guinamard et al. 2011 for review). While it is not considered as a canonic voltage-gated channel, its activity increases with membrane depolarization. This results in a typical outward rectification of the whole-cell current. Channel open probability is also finely regulated by internal Ca2+ concentration. Ca2+ activates the channel with a concentration for half efficiency in the range of few μmol.L−1 (Ullrich et al. 2005). TRPM4 is inhibited by internal adenosine nucleotides (ATP, ADP, AMP) with a concentration for half maximal inhibition in the range of the μmol.L−1 (Ullrich et al. 2005; Mathar et al. 2014 for review). Note that this point is a major discrepancy with the TRPM5 channel which also produces an NSCCa current but which is not sensitive to adenosine nucleotides (Ullrich et al. 2005).

Beside of these major regulations, TRPM4 current has also been shown to be activated by phosphatidylinositol 4,5-bisphosphate (PIP2) which uncouple channel activity from voltage variations and increases sensitivity to Ca2+. PKC and oxygen species such as H2O2 also increase TRPM4 activity (for reviews, see Mathar et al. 2014; Guinamard et al. 2011).

Identification of TRPM4 roles in physiology requires pharmacological modulators. However TRPM4 still lacks specific modulators. It is inhibited by the nonsteroidal anti-inflammatory drug flufenamic acid with a concentration for half maximal inhibition, IC50 = 3 × 10−6 mol.L−1. Albeit flufenamic acid is known to target a large range of other ion channels, TRPM4 is among the more sensitive. Spermine and kinin also inhibit the channel (Ullrich et al. 2005). Interestingly, the antidiabetic sulfonylurea glibenclamide inhibits TRPM4 (for reviews, see Mathar et al. 2014; Guinamard et al. 2011), a property which opens potential clinical applications as described in the section named “TRPM4 as a New Drug Target for Drug Design”. To date, the most specific inhibitor is the hydroxytricyclic compound 9-phenanthrol (IC50 = 2 × 10−5 mol.L−1) (Grand et al. 2008).

TRPM4 Partners Proteins

TRPM4 has been shown to co-localize and physically bind with TRPC3 in HEK-293T transfected cells (Cho et al. 2015 for review). While such association generates a current which properties do not strictly match those of TRPM4 or TRPC3, it is not clear whether the complex is an association of the two proteins or a heteromerization of TRPM4 and TRPC3 in a single heterotetramer. Moreover, the association remains to be confirmed in native cells. Nevertheless, it opens the possibility that TRPM4 associates with other TRP isoforms to form specific channels.

It has also been shown that TRPM4 heteromerizes with the sulfonylurea receptor 1 (SUR1). The complex confers to TRPM4 a higher sensitivity to ATP and glibenclamide and increases its affinity for Ca2+ and calmodulin. The TRPM4-SUR1 complex inhibition has been shown to reduce neuroinflammation in subarachnoid hemorrhage in human, paving the way for glibenclamide use to protect against brain injuries following ischemic stroke (see Caffes et al. 2015 for review).

Partner proteins have also been shown to modulate TRPM4 trafficking. The binding protein 14-3-3γ association with TRPM4 at the N-terminus increases forward trafficking to the plasma membrane, as shown in HEK-293T cells and in HT22 cells, a phenomenon involved in glutamate-induced neuronal cell death (Cho et al. 2015 for review).

TRPM4 may also associate with small ubiquitin-like modifier (SUMO) family members. Channel deSUMOylation is involved in channel reinternalization after expression to the plasma membrane. A mutation in the N-terminus (E7K) has been identified in a patient with cardiac conduction block and shown to be responsible for increased SUMOylation and thus decrease in channel reinternalization (Kruse et al. 2009). Such endocytosis is also affected by other mutations (R164W, A432T, G844D) identified in additional patients with cardiac conduction blocks (see Guinamard et al. 2015 for review) and associated to deregulation of SUMOylation.

TRPM4 Physiological Significance

The wide mRNA detection within tissues (Launay et al. 2002; Nilius et al. 2003) and the functional recording of TRPM4-like currents in most of the cells where it has been looked for let suspect a large spectrum of physiological implications. Indeed, TRPM4 has been shown, since 15 years, to be involved in numerous processes. Given the wide range of implication of TRPM4, we will refer, in the following lines, to specific reviews to drive the reader.

Physiological/pathological effect of TRPM4 first comes from its ionic selectivity. It is a monovalent cation channel and thus mainly leads to Na+ and K+ fluxes through the plasma membrane. However, according to the negative resting membrane potentials and ionic distributions, activation of TRPM4 mainly produces an inward Na+ current in about all cells. It thus leads to membrane depolarization. Another key element is the fact that TRPM4, which is a Ca2+-activated cation channel, is able to transform a cytosolic Ca2+ variation into a voltage variation (Fig. 2). Two complementary phenomena can result from this voltage variation: (a) a modification of voltage-gated channel activity and (b) a modification of the electrochemical driving force for ion movements across the plasma membrane. These two phenomena have opposite effects on Ca2+ entry since opening of voltage-gated Ca2+ channels favors Ca2+ entry while cell depolarization decreases the driving force for Ca2+ entry. The global effect on Ca2+ flux on specific tissues thus depends on the pattern of Ca2+-permeable proteins expressed in each cell type. Because TRPM4 modulates Ca2+ entry and is regulated by Ca2+ entry and/or Ca2+ release from the intracellular stores, it appears to be a drive belt in Ca2+ signaling.
TRPM4, Fig. 2

TRPM4 in Ca2+ signaling. Relations between TRPM4 and Ca2+ signaling. TRPM4 is activated by cytosolic Ca2+. According to this, Ca2+ entry through Ca2+ transporters, voltage-dependent Ca2+ channels (VDCa), or any other types of Ca2+ channels, as well as Ca2+ release from intracellular stores, leads to TRPM4 opening. TRPM4 opening produces a nonselective monovalent cationic current which is mainly represented by Na+ entry, according to the resting membrane potential and ion equilibriums in physiological conditions. Na+ entry produces cell depolarization which reduces electrochemical driving force (ΔΨ) for Ca2+ entry. In addition, such depolarization modulates the activity of voltage-dependent channels (VD channels) in cells expressing those proteins. External stimulation which modulates any of these actors turns on or off this system. As an example, a G-protein-coupled receptor (GPCR) is represented, with the phospholipase C (PLC) pathway which leads to endoplasmic reticulum depletion. Vm membrane potential

TRPM4 in Immune Cells

TRPM4 has been first shown to modulate the immune response by preventing Ca2+ overload in a variety of immune cells such as dendritic cells, T lymphocytes, mast cells, monocytes, and macrophages in which Ca2+ signaling is a ubiquitous signaling mechanism. This has been demonstrated using TRPM4 interference RNA or TRPM4 knockout mice (Barbet et al. 2008; Vennekens et al. 2007; Mathar et al. 2014 for reviews). In T lymphocytes, TRPM4 acts by decreasing the electrochemical driving force for Ca2+ entry since the inward Na+ current through TRPM4 depolarizes the plasma membrane (Fig. 3a). By so, it reduces the Ca2+ release-activated current (CRAC) responsible for the increase in intracellular Ca2+. Consequently the activation of the nuclear factor of activated T cell (NFAT) which modulates gene transcription is reduced, inducing a drop in secreted factors amounts. In those cells, a ping-pong action between depolarizing current induced by TRPM4 opening and Ca2+ entry through CRAC participates in the development of cytosolic Ca2+ waves. TRPM4 also influences the immune response by modulating the migration of dendritic cells.
TRPM4, Fig. 3

Physiological roles of TRPM4. TRPM4 participates in immune cell signaling (a), electrical activity of pacemaker cells from cardiac sinus node (b), insulin secretion by pancreatic β-cells (c), contraction of cerebral arteries smooth muscle cells (d), and breathing rhythm generation in the pre-Bötzinger complex from the brainstem (e). Abbreviations: Ag antigen, AMPA-R γ-amino-3-hydroxyl-5-methyl-4-isoxalone-propionate receptor, Cx connexin, DAG diacylglycerol, ΔΨ electrochemical driving force, ER endoplasmic reticulum, GLUT glucose transporter, GPCR G-protein-coupled receptor, HCN hyperpolarization and cyclic nucleotide-activated channel, IP 3 inositol 1,4,5-triphosphate, IP 3 R IP3 receptor, K ATP ATP-dependent potassium channel, mGLU-R metabotropic-glutamate receptor, NCX sodium/calcium exchanger, NFAT nuclear factor of activated T cells, Orai 1 calcium release-activated calcium modulator 1, PIP 2 phosphatidylinositol 4,5-biphosphate, PKC protein kinase C, PLC phospholipase C, RyR ryanodine receptor, SR sarcoplasmic reticulum, STIM stromal-interacting molecule, SUR sulfonylurea receptor, TCR T-cell receptor, TRPC6 transient receptor potential canonical 6, TRPM4 transient receptor potential melastatin 4, Tyr-K tyrosine kinase, VDCaC voltage-dependent calcium channel, VDKC voltage-dependent potassium channel, VDNaC voltage-dependent sodium channel, Vm membrane potential, VR vasopressin receptor

TRPM4 in Heart

Heart expresses a high level of TRPM4 mRNA (Launay et al. 2002) with the greatest expression in the conductive tissue, moderate in the atria, and the lowest in the ventricle (see Guinamard et al. 2015 for review). The same gradient has been observed for functional TRPM4 currents. Physiologically, TRPM4 has been shown to support the pacemaker activity of the sinus node cells (Fig. 3b) and prolong Purkinje fibers as well as atrial and ventricular cardiomyocyte action potentials. It is also involved in cardiac dysfunctions since inherited TRPM4 mutations have been found in families with members showing cardiac conduction blocks or Brugada syndrome (Fig. 1) (Kruse et al. 2009; Guinamard et al. 2015 for review). Most of these mutants lead to a variation (gain or loss) in TRPM4 current density at the plasma membrane when heterologously expressed in HEK-293 cells. These variations are due to modifications of TRPM4 protein expression at the plasma membrane, while single-channel electrophysiological properties are not affected. However, the mechanistic by which channel mutation leads to the specific cardiac disease is not well understood, and current modifications remain to be confirmed in cardiomyocytes. TRPM4 also participates in hypoxia-reoxygenation-induced arrhythmias. Finally TRPM4 might also be involved in the control of cardiac hypertrophy since TRPM4 knockout mice develop such hypertrophy due to hyperplasia (Guinamard et al. 2015 for review).

TRPM4 in Insulin Secretion by Pancreatic β-Cells

In addition to other channels, TRPM4 modulates insulin secretion by pancreatic β-cells from the islets of Langerhans (Fig. 3c). In those, TRPM4, activated by cytosolic Ca2+ increase or the PLC/PKC pathway, would depolarize the cells, producing an activation of voltage-gated Ca2+ channels. Such activation increases Ca2+ entry necessary for the fusion of internal vesicles with the plasma membrane and thus insulin secretion (see Islam 2011 for review; Shigeto et al. 2015). In this signaling, TRPM4 might be a link between Gq-coupled receptors which activates the PLC/PKC pathway and insulin secretion, as it has been shown for the vasopressin-induced insulin secretion.

TRPM4 in Smooth Muscle Cells

TRPM4 modulates the activity of a variety of smooth muscle myocytes (see Earley 2013 for review). In those cells, Gq-coupled receptor activation leads to IP3 receptor opening and Ca2+ release from sarcoplasmic reticulum which activates TRPM4. Na+ entry through TRPM4 produces a depolarization which opens the voltage-dependent Ca2+ channel (VDCA) allowing Ca2+ entry initiating cell contraction. This has been first observed in cerebral arteries (Fig. 3d) where TRPM4 acts as a bridge in the mechanosensation that leads to vasoconstriction according to the Bayliss effect. More recently, TRPM4 has been shown to promote the contraction of the detrusor smooth muscle of the urinary bladder (Hristov et al. 2016). Finally, TRPM4 is also expressed in colonic smooth muscle, but its physiological implication remains to be evaluated (see Earley 2013 for review).

TRPM4 in Neurons

TRPM4 participates in neuronal activity. In that field, TRPM4 implication has been mostly investigated in the context of the onset of breathing activity by pacemaker neurons from the pre-Bötzinger complex located in the brainstem (see Funk 2013 for review). In this region, an inspiratory neuronal network involves glutamatergic transmission through AMPA receptors and metabotropic receptors (Fig. 3e). Gq-coupled metabotropic receptors activate the PLC/IP3 pathway, leading to intracellular Ca2+ stores release and TRPM4 activation. The resulting TRPM4-depolarizing current enhances bursting activity of pacemaker neurons, in combination with other depolarizing currents induced by the voltage-dependent Ca2+ channels and AMPA receptors.

TRPM4 as a New Target for Drug Design

Since it is involved in a large variety of physiological processes and their malfunctions, TRPM4 is now considered as an interesting drug target in medicine. However, little is known about the feasibility of its modulation in the aim to correct such malfunctions. An increasing work has been done recently on central nervous system injuries and their treatments by glibenclamide which is known to inhibit the SUR1-TRPM4 complex (see Caffes et al. 2015 for review). The complex is overexpressed in neurons, astrocytes, oligodendrocytes, and vascular endothelial cells in focal ischemia and hemorrhage. In these pathologies, Ca2+ overload results in cell death. Thus SUR1-TRPM4 expression may be beneficial in a first step since the resulting current decreases Ca2+ overload by reducing the electrochemical driving force for Ca2+ entry. However, it becomes noxious with time since Na+ entry through TRPM4 leads to Na+ overload followed by cellular edema which may terminate in cell membrane rupture, as occurs in necrosis. According to this, pharmacological inhibition of SUR1-TRPM4 by glibenclamide was hypothesized to have neuroprotective properties. This point is still under consideration, but promising results have already been obtained in human in the context of ischemic and hemorrhagic stroke (Sheth et al. 2016).

According to the complex but strong contribution of TRPM4 in cardiac physiology and dysfunctions, including arrhythmias (see Guinamard et al. 2015 for review) as well as in vascular functions, the channel has also to be considered as a valuable target in cardiovascular disease correction. However, to date, no clinical data are available.

Summary

Transient receptor potential, subfamily M(melastatin-related), member 4 (TRPM4) gene encodes a channel protein with the classical molecular structure of TRP channels. TRPM4 mRNA, protein, and current have been detected in a large range of tissues, including excitable and non-excitable cells in human. TRPM4 channel is permeable to monovalent cations (Na+ and K+) but not Ca2+. It is activated by cytosolic Ca2+, PIP2, protein kinase C, and membrane depolarization but inhibited by internal ATP. According to these properties, TRPM4 opening leads to a depolarizing current due to Na+ entry in most of the cells. Thereby, it modulates the activity of voltage-dependent ion channels and the electrochemical driving force for ions. Since it is activated by cytosolic Ca2+, TRPM4 is a driving belt in internal Ca2+ signaling by transforming cytosolic Ca2+ variations into voltage variations.

A number of physiological roles have been described for TRPM4. In the immune system, it reduces immune factors secretion by T lymphocytes and influences dendritic cells migration. In the heart, it participates in the induction of pacemaker activity in the sinus node cells and prolongs action potentials from cardiomyocytes. It also enhances the onset of breathing activity by pacemaker neurons from the pre-Bötzinger complex located in the brainstem. TRPM4 influences insulin secretion by pancreatic β-cells. Finally, TRPM4 modulates the activity of a variety of smooth muscle myocytes including those from the vasculature and the detrusor muscle from the bladder.

TRPM4 has also been shown to be involved in pathologies. TRPM4 gene mutations leading to either loss or gain of function were found in patients with cardiac conduction blocks and Brugada syndrome. In addition, TRPM4, in combination with the sulfonylurea receptor type 1, promotes brain injuries in the context of ischemia. According to these implications, TRPM4 is now considered as a new promising target in cardiac or neuronal protection as well as in other tissues damages. A first therapeutic study targeting TRPM4 by pharmacological modulators is on the way in the context of neuroprotection.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Romain Guinamard
    • 1
  • Christophe Simard
    • 1
  • Laurent Sallé
    • 1
  1. 1.Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardiqueNormandie Univ, UNICAENCaenFrance