The TRP Channels Serving as Chemical-to-Electrical Signal Converter

Yuhua Tian; Jie Zheng

doi:10.1152/physrev.00012.2024

. Author manuscript; available in PMC: 2025 Jul 1.

Published in final edited form as: Physiol Rev. 2025 Jan 15;105(3):1033–1074. doi: 10.1152/physrev.00012.2024

The TRP Channels Serving as Chemical-to-Electrical Signal Converter

Yuhua Tian ^1,², Jie Zheng ^2,^¶

PMCID: PMC12186708 NIHMSID: NIHMS2086617 PMID: 39813402

Abstract

Biology uses many signaling mechanisms. Among them, calcium and membrane potential are two prominent mediators for cellular signaling. TRPM4 and TRPM5, two calcium-activated monovalent cation-selective ion channels, offer a direct linkage between these two signals. Their activities convert a rise in the intracellular calcium level—a chemical signal—into depolarization of membrane potential—an electrical signal. Interestingly, membrane depolarization can in turn alter the electrical driving force or membrane permeability for calcium entry, hence offers feedback mechanisms for regulating calcium signaling. By converging two powerful cellular signals, TRPM4 and TRPM5 can contribute to many fundamental biological processes including cardiovascular biology, immunology, insulin release, chemo-sensation, and others. Numerous mutations in TRPM4 are linked to human hereditary cardiac and skin diseases, whereas knocking out TRPM5 in mice abolishes perception of sweet, umami and bitter tastes. This review summarizes what are currently known about the signaling roles of these unique TRP channels, and what remain mysterious.

Keywords: calcium signaling, membrane potential, activation gating, PIP2, cardiac physiology, insulin release, immune response, skin disease

1. Introduction

Life is a balance between homeostasis (maintaining a stable biological state) and short- or long-term changes (1). To orchestrate this dynamic balance, communication between organs, tissues, cells, and molecules is essential. Among numerous means of biological communication, calcium ions stand out as a universal mediator for signaling (2, 3). Virtually all cell types utilize calcium ions to switch on and off gene translation, trigger protein conformational arrangements, drive cell contraction and migration, induce or terminate inter-molecular interactions, administrate trafficking and secretion, and so on. Specialized organelles and proteins have emerged over the course of evolution to detect, capture, store, and release calcium ions. Calcium signaling works at all scales, from the systematic level to the subcellular and molecular levels. Membrane potential, as a product of asymmetrical ion distribution across biological membrane that is permeable to them, exists also in all living cells. It contributes to dynamic functions of excitable cells; for example, changes in membrane potential constitute the basic language for the nervous system, the master control of muscle contraction, and the switch for fertilization and immune response. In non-excitable cells and intracellular organelles, membrane potential plays a crucial role in influencing a wide range of cellular physiology such as cross-membrane transport and ATP synthesis. Even single-cell organisms have evolved to utilize these two prominent signaling systems.

It should therefore come as no surprise that these two signaling systems in biology do not operate independently. Connecting them presents obvious and powerful advantages. Communication between calcium ions and membrane potential occurs in both directions. Negative membrane potential serves as a strong driving force for influx of divalent cations like calcium (e.g., through Orai/STIM channels), and a barrier for its outward transport across the plasma membrane (e.g., by sodium-calcium exchanger NCX). A similar situation applies to intracellular organelles (4). Membrane depolarization reduces the driving force for calcium influx; however, when reaching a sufficiently high level, it can open voltage-gated Cav channels to allow rapid calcium influx. Calcium ions in turn regulate membrane potential in several ways. Transmembrane calcium flux by itself can alter membrane potential if it is at a sufficiently high rate (such as that seen during a cardiac action potential). Calcium ions also switch on or inhibit the transmembrane flux of cations and anions to shift membrane potential, often rapidly and powerfully. Calcium can shift membrane potential in either direction, depolarization or hyperpolarization. Calcium ions hyperpolarize the membrane when they activate, either directly by binding or indirectly through calcium-binding proteins, calcium-activated chloride channels and several potassium channels including large-conductance potassium (BK) and small-conductance potassium (SK) channels. Calcium can also depolarize the cell membrane. This is achieved by activating the TRPM4 and TRPM5 channels^*.

2. The CAN channels and their molecular cloning

The existence of calcium-activated channels with an elevated reversal potential has been known for a long time. Calcium-activated, depolarizing currents were observed in cardiomyocytes (5) (Figure 1A&B), Purkinje tissue (6, 7), neuroblastomas (8), and others. These currents are not carried by calcium per se, whose equilibrium potential is the most positive among ions relevant to electrophysiology and far from the reversal potential of the observed calcium-induced current, at near zero millivolt (9, 10). Based on the same rationale, the depolarizing currents also cannot be mediated by sodium alone but jointly by sodium and potassium under physiological conditions (Figure 1B). Therefore, the channels responsible for mediating these currents are nonselective among monovalent cations, and hence were referred to as CAN (calcium-activated nonselective) channels before their identities have been revealed. Depolarizing currents exhibiting features associated with the CAN channels have been observed broadly in many cell types, though they may appear to vary in certain properties; for example, some may be long-lasting whereas others transient (11). The calcium concentrations required to activate this type of currents were generally found to be in the low micromolar range.

Figure 1. — Representative current traces and I-V relationships of the CAN channels and cloned TRPM4 and TRPM5 channels. A&B, Example single-channel recordings of calcium-activated non-selective cation channels from cultured cardiac cells (A) and their I-V relationship (B). Recording voltage was −70 mV; intracellular calcium concentration was 6 μM (top), 1.5 μM (middle), and zero μM (bottom). Filled circles and open squares in B are data points with symmetrical sodium saline solutions and with intracellular potassium/extracellular sodium saline solutions, respectively, with reversal potentials around zero mV. Reproduced from Colquhoun et al. (5); used with permission under CC-BY license. C&D, TRPM4 single-channel currents activated by 0.3 μM calcium (C) and their I-V relationship with intracellular potassium/extracellular sodium saline solutions (D), with a reversal potential around zero mV. Reproduced from Launay et al. (13) with permission. E&F, TRPM5 currents activated by 12 μM calcium (E) and the I-V relationship (F). Reproduced from Liu and Liman (20) with permission.

One of the first ion channels with characteristics of the CAN channels was cloned from human cDNA libraries at the turn of the century (12). Shortly after, a longer form was identified (13) (Figure 1C&D). Based on sequence similarities, this new channel fits in the TRPM subfamily of the transient receptor potential (TRP) channel family, which is a large group of cation channels that exhibit the common feature as cellular sensors for diverse environmental stimuli as well as internal signaling (14). The short and long variants were named TRPM4a and TRPM4b, respectively. A variant shorter than TRPM4a was later found, and named TRPM4c (15). These variants differ in the length of their intracellular N-terminal segment. Rat TRPM4a and TRPM4b isoforms have been identified (16); only one mouse TRPM4 gene, corresponding to human TRPM4b, has been identified (15). TRPM4b (often referred to simply as TRPM4) is the predominantly studied form and the one discussed in this review. A close homolog of TRPM4 was cloned a little earlier (17), which was originally named MTR1 but later renamed TRPM5 due to its close resemblance in sequence and functional properties to TRPM4 (18) (Figure 1E&F). There are now eight members of the TRPM subfamily; among them only TRPM4 and TRPM5 are calcium-activated non-selective monovalent cation channels (19). TRPM4 exhibits a permeability sequence of Na⁺ ~ K⁺ > Cs⁺ > Li⁺, with no permeability to divalent cations (13). TRPM5 is equally permeable to Na⁺, K⁺, and Cs⁺ but not to Ca²⁺ (20). At very high concentrations, intracellular calcium ions actually inhibit TRPM4 current (21).

3. Structural features of TRPM4 and TRPM5

TRPM4 and TRPM5 were predicted by sequence analysis to be tetrameric channels like most other TRP channels. They have intracellularly located N and C termini, six transmembrane segments (S1 to S6), and a re-entry loop between the fifth (S5) and sixth (S6) transmembrane segments that contributes to the formation of the ion permeation pore and the ion selectivity filter. This topological prediction was confirmed when high-resolution structures of TRPM4 (22–26) and TRPM5 (27, 28) became available (Figure 2A). Homotetrameric channels are formed in a four-fold symmetric, domain-swapped architecture, meaning that the S1-S4 “voltage sensor like domain” of one subunit directly interacts with the S5-S6 pore-forming domain of a neighboring subunit. Most of the protein mass is located intracellularly, where potential interaction domains with regulatory proteins and small molecules have been proposed.

Figure 2. — Structural features of TRPM4 and TRPM5 revealed by cryo-EM. A. Overall structure of TRPM4 (PDB ID 9B8Y, left panel) and TRPM5 (7MBQ, right panel). The light green spheres represent bound Ca²⁺ ions. TMD, transmembrane domain; ICD, intracellular domain; MHR, melastatin homology region. B. The binding pocket of decavanadate (DVT, cyan) in TRPM4 (9B8Y). Two neighboring subunits are colored in magenta and gray, respectively. Key positively charged residues in direct contact with DVT are highlighted. C. The closed states and open states of TRPM4 and TRPM5 (PDB ID from left to right: 6BQR, 9B8Y, 7MBR, and 7MBQ), highlighting the ion permeation pore. S5 and S6 represent the fifth and sixth transmembrane helices, respectively.

Multiple functional domains within the channel proteins have been identified. The intracellular N-terminal segment of TRPM4 contains an end-binding (EB) protein binding motif (SWIP) that mediate TRPM4-EB interaction and trafficking (29). There are also four melastatin homology regions (MHR1–4) in the N-terminal segment, with MHR1 and MHR2 forming an intact domain structure and MHR3 connecting MHR1/2 and MHR4 (23) (Figure 2A). MHR1/2 forms extensive interactions with MHR3 of the same subunit and MHR3 of an adjacent subunit. Within this domain, densities corresponding to ATP and decavanadate (one of three sites) have been observed (22, 23). The C-terminal region of TRPM4 consists of a coiled-coil helix with a segment extending nearly parallel to the membrane which then bends about 120° into vertical helices that are parallel to the vertical helices of the other subunits. The C-terminus has been previously proposed to contain modulation sites for PIP2, calmodulin binding, phosphorylation, and is important for tetrameric formation (30–32). In addition, functional studies suggested decavanadate regulates TRPM4 activation by binding to its C-terminal domain (33). Indeed, structural studies observed a second decavanadate binding site at the positively charged hinge of the C-terminal coiled-coil domain (23). Previous functional studies observed that the presence of decavanadate increased sensitivity of TRPM4 to ATP inhibition (33). Thus, the binding of decavanadate to the C-terminal domain is consistent with this site being involved in the positive modulation effects as it should not competitively antagonize ATP binding to the N-terminal site. A third decavanadate binding site, at the interface between the intracellular domain and transmembrane domain, was found in a new TRPM4 structure when the protein samples were prepared at the physiological temperature (37°C) (26)(Figure 2B). Only in the presence of this decavanadate and calcium ions a large fraction of the TRPM4 proteins kept at 37°C resided in the open state.

Directly relevant to the calcium-sensing function of TRPM4 and TRPM5 channels are the proposed calcium-binding sites (Figure 3). One set of calcium-binding sites were first identified when the cryo-EM structures of TRPM4 were solved (24). Located within the membrane-spanning domain formed by the S1-S4 segments and close to the intracellular side of the membrane, these calcium-binding sites stood out as they were empty in the absence of divalent cations but were occupied by a density resembling a calcium ion when 5 mM calcium were present during sample preparation (24) (Figure 3A&B). Each of the transmembrane calcium-binding site is surrounded by four acidic or polar residues; in human TRPM4, these residues are E828, Q831, N865, and D868. When a higher resolution structure of TRPM5 (at 2.3 Å) became available, a conserved binding site was also observed in each subunit, formed by E768, Q771, D797, and N794 of the zebrafish TRPM5 (27). Two water molecules could be identified in the binding site to join the four residues as calcium-coordinating ligands (27), hence satisfying the octahedral coordination chemistry for a calcium ion (34). Interestingly, equivalent cation binding sites are also found in other TRPM channels and even TRPC channels that are not particularly activated (but are positively regulated) by calcium ions (Figure 3A&B) (35, 36). A pathway connecting the transmembrane calcium binding site to the intracellular milieu for the entrance and exit of calcium ions can be envisaged in the TRPM4 structure, indicating that occupation of the binding site by calcium (and likely other cations under experimental conditions) can be a dynamic process (24). This calcium entrance pathway is seen in TRPM5 as well (27).

The TRPM5 structures offer exciting new insights into the Ca²⁺ activation mechanism (27). Unlike all the previously available TRPM4 structures, the Ca²⁺-bound TRPM5 structure is thought to represent an open state, with the hydrophobic gate at lower S6 widened substantially compared to the apo (closed) state. An allosterically coupled regulatory site for Ca²⁺ is also identified in each subunit. This second calcium binding site is located intracellularly at the interface between the MHR1/2 and MHR3/4 domains (Figure 3C&D); binding of Ca²⁺ to this site causes local conformational rearrangements of the MHR domains. Apparently, the effect of Ca²⁺ binding to the intracellular site can be felt at the transmembrane Ca²⁺-binding site some 70 Å away, yielding a substantially increased apparent binding affinity and positive allosteric regulation for channel activation.

It turns out that TRPM4 also persists an intracellular Ca²⁺-binding site equivalent to that of TRPM5, at the interface between MHR1/2 and MHR3/4 (26) (Figure 3C&D). This site could be observed when the protein samples were first warmed to physiological temperatures before rapid freezing. To form this site, there are substantial rearrangements in MHR1/2 and MHR3/4 from the closed state structure. The observations of two Ca²⁺-binding sites and substantial structural changes in the intracellular domain suggest that activation gating of TRPM4 and TRPM5 may share similar structural mechanisms involving large conformational rearrangements. Interestingly, TRPC channels contain one or two intracellular calcium binding sites; calcium binding to these sites allosterically regulates channel activities (36).

Like many cation channels (37), TRPM4 and TRPM5 have an ion permeation pore whose architecture resembles two hourglasses fused together—the hourglass on the top is formed by the re-entry loops from the four subunits surrounding the pore in a symmetric arrangement; the hourglass on the bottom is formed by the S6 segments also in a symmetric arrangement (Figure 2C). A hydrophobic residue in S6 (I1040 in TRPM4; I966 in TRPM5) is located at the neck of the bottom hourglass. Activation gating involves widening of this restriction, as can be visualized by comparing the apo and calcium-bound TRPM5 structures (27). A hereditary skin disease mutation at this point (I1040T), to be discussed later, makes the TRPM4 channel easier to open. At peripheral positions the pore is surrounded by the S5 segments, which are in turn pinched by the S4-S5 linkers that extend to the transmembrane calcium-binding pocket in each subunit. The post-S6 segment forms a helical structure underneath the S4-S5 linker. Named TRP helix, this segment has a highly conserved sequence among TRP channels (38). The TRP helix of TRPM4 and TRPM5 (and many other TRP channels) is highly sensitive to structural perturbations such as those produced by mutations, suggesting a steady role in supporting the conformation stability of the pore and even a dynamic role in transducing stimuli to the activation gate (39).

The top hourglass structure is where ion selection mainly occurs. A short segment from each subunit forms the narrowing (the hourglass neck) that is the ion selectivity filter (Figure 2C). Residues of the TRPM4 and TRPM5 ion selectivity filters point their sidechain inwards to directly interact with permeant ions. For highly potassium-selective channels, the ion selectivity filter residues bury their sidechain inside and form interactions with surrounding residues to stabilize the pore architecture while exposing their backbone oxygen atom for interaction with permeant potassium ions (40). Above the selectivity filter, a gradually widening outer pore entrance helps funnel permeant ions into the ion selectivity filter. Acidic residues lining the surface of this entrance likely attract cations into this space via electrostatic forces. TRPM4 and TRPM5 of various species normally exhibit a single-channel slope or chord conductance in the 16-to-25 pS range (13, 20, 41, 42).

4. Activation and desensitization

Activation of TRPM4 and TRPM5 exhibits clear calcium-concentration dependence (Figure 4 A&B). The Hill slope of their calcium concentration dependence curve is steeper than one, suggesting the likelihood that calcium ions bind to all four subunits cooperatively to promote channel activation (20, 43, 44). In excised inside-out patches, TRPM4 channels have been generally found to exhibit an increase in activity when the intracellular calcium concentration reaches 100 μM or higher (43, 44). Whole-cell recordings showed a much higher calcium sensitivity, but the obtainable current amplitudes did not seem to be proportional to what were recorded from cell-free membrane patches (43, 44). The high concentrations of calcium ions needed for observing channel activation from cell-free patches is concerning. A speculative view is that perhaps TRPM4 channels are juxtaposed next to calcium entry or release sites, where the local calcium concentration might reach a level sufficiently high to induce meaningful TRPM4 activities under physiological conditions. Alternatively, the channels been recorded in expression systems might lack certain cofactor(s), or perhaps they have quickly gone through functional changes such as desensitization, which has been demonstrated to reduce the channel’s calcium sensitivity (30, 44) (Figure 4A–C).

What might be the source of calcium increase that activates TRPM4 and TRPM5 under physiological conditions? While in most cases the question remains to be answered, sceneries such as release from intracellular calcium store and influx from extracellular milieu have been considered. In taste cells, an increase in calcium concentration is likely due to release from the intracellular store as a downstream event of the phospholipase C (PLC) signaling pathway (45). A major task for future research is to identify the calcium source in various tissues and cell types where TRPM4 and TRPM5 activities have been observed. The functional roles of the two sets of calcium binding sites remain to be determined, as well as how calcium binding leads to channel activation.

At non-physiologically high calcium concentrations, TRPM4 currents exhibit a transient peak upon both calcium application and removal (46). The presence of these transient current peaks indicates the possible existence of a calcium-dependent inhibition process and the likelihood that recovery from this inhibition upon removal of calcium occurs faster than channel deactivation upon calcium removal. How much this inhibition process helps shape the calcium response of TRPM4 at physiological concentrations remains to be determined. At even higher calcium concentrations (>1 mM), which would reduce the amplitude of the steady state current through apparent pore block (21), an additional mysterious third peak emerges after the second peak (47). This peak diminishes as the channel desensitizes, indicating a likely shared mechanism.

As mentioned above, desensitization of TRPM4 and TRPM5 can substantially alter their calcium responses. Both the current amplitude and the kinetic properties change upon desensitization. Desensitized channels respond to a step increase in intracellular calcium concentration much slower than naïve channels but deactivate much faster upon calcium removal (44). These changes in kinetic properties may contribute or even underlie the observed decline in stable current amplitude during channel desensitization. The third transient peak mentioned above also drops in amplitude, and even disappears, upon extensive desensitization (47). TRPM5 channels of mammalian species desensitize much faster than zebrafish TRPM5 (28). While desensitization of TRPM4 and TRPM5 appears to be a complex process, one well-established cause for desensitization is depletion of PIP2. This will be discussed in detail later. Treatment with hydrogen peroxide can also remove TRPM4 desensitization (48).

So far, intracellular calcium is the only known biological activator for TRPM4 and TRPM5. It remains an open question whether other biologically relevant molecules can activate these channels. TRPM5 is not activated by 1-oleoyl-2-acetyl-sn-gylcerol (OAG), an analog for diacylglycerol (DAG), at 100 μM, or IP3 at 10 μM (20, 44). While PIP2 plays an important role in maintaining calcium-induced activation, by itself PIP2 does not activate TRPM4 or TRPM5.

5. Channel regulation mechanisms

Like most ion channels, TRPM4 and TRPM5 are dynamically regulated under physiological and pathological conditions. Rich information on regulation of TRPM4 and TRPM5 activities has been accumulated through extensive research. These channels are known to be sensitive to regulatory lipids such as PIP2, calmodulin, temperature changes, and even the transmembrane voltage their activity regulates. Many agonists and antagonists have been identified and studied over the years. For example, extracellular protons have two types of inhibitory effects on TRPM5: they reduce current by an apparent blockade mechanism and an inactivation mechanism (49). These two effects are related but distinct; mutations to an acidic residue (E830) in the S3-S4 linker and a histidine residue in the pre-S6 loop (H934) of the mouse TRPM5 both simultaneously reduce proton-dependent block and inactivation, whereas a mutation to another histidine residue in the after-S5 loop spared acid block but caused significant recovery from acid-enhanced inactivation. Here we summarize what are known about channel regulation mediated by the membrane potential, calmodulin, PIP2, ATP, protein kinase C (PKC), polyamine and temperature.

a. Membrane potential

While TRPM4 and TRPM5 serve as calcium-activated effectors through altering the electrical potential of the plasma membrane, their calcium sensitivity is in turn regulated by membrane potential. At a constant intracellular calcium concentration, the amplitude of TRPM4 and TRPM5 currents recorded from a cell or macro-patch increases super-linearly upon membrane depolarization (Figure 4C). This change can be observed within the physiologically relevant voltage range. For TRPM4, the half-activation voltage, V_1/2, defined as the voltage where activity reaches 50% of its peak level, is measured (by fitting the normalized current-voltage relationship to a Boltzmann function) at room temperature to be 25 mV when 100 μM calcium was present (15). The voltage-dependent activation curve shifts leftward at higher calcium concentrations or temperatures. For TRPM5, the V_1/2 value appears to be even more negative, which reflects its higher calcium sensitivity (20, 43). Hence, a physiological role can be predicted for the dynamic regulatory process by voltage. The single-channel currents of cloned TRPM4 and TRPM5 channels exhibit a near ohmic dependence on voltage, at a conductance level of about 20 pS (13, 15, 20, 41, 42). The super-linear increase in macroscopic current amplitude in response to depolarization is therefore due to an increase in channel open probability. This voltage dependence produces strong outward rectification of the macroscopic current (15). Voltage sensitivity of TRPM4 and TRPM5 channels are rather weak when compared to the Kv and Nav channels involved in action potential firing. The effective gating charge estimated from published data is less than one elementary charge (e₀), whereas for Kv channels the value is 13 to 16 e₀ (50).

The voltage-sensing mechanism of TRPM4 and TRPM5 is still unknown. Given the weak voltage sensitivity, the voltage sensor can reside in many possible channel structures (51). Many other TRP channels exhibit comparable voltage sensitivity. For TRPV1, the voltage sensing mechanism involves extracellular structures (52); for TRPM8, a charged residue near the bottom of the fourth transmembrane segment S4 serves as the voltage sensor (53). Voltage regulation serves as a positive feedback mechanism for TRPM4 and TRPM5, as the channel activity increases upon depolarization.

b. Calmodulin

Given the precedence that calcium activation of the SK channels is mediated by the calcium-sensor calmodulin instead of direct binding of calcium to the channel protein (54), it was attempting to envision that TRPM4 and TRPM5 could be activated in a similar manner. This however turned out to be unlikely (30, 41). Nonetheless, calmodulin was found to play a role in dynamically regulating TRPM4 activity (30, 55) (Figure 4D). Introducing a mutant version of calmodulin that cannot bind calcium (CaM_1,2,3,4) substantially reduced, but however did not eliminate, TRPM4 current. Supplying recombinant calmodulin to cell-free patches could slow down channel desensitization and reduce its extent (30). Nonetheless, divalent cations Mn²⁺, Ni²⁺, and Co²⁺ were found to comparably potentiate calcium induced TRPM4 currents, even though the latter two have no effect on calmodulin (55). Sequence analysis suggested several candidate calmodulin binding sites in the N- and C-terminal of TRPM4; deletions of these sequences led to reduction of channel current (30). There is currently no TRPM4-calmodulin complex structure.

Multiple lines of evidence suggest that TRPM5 is not activated or modulated by calmodulin (41): (1) Ba²⁺ ions alone at concentrations as high as 10 mM, which is expected to stimulate calmodulin, could not activate TRPM5; (2) the calmodulin inhibitor calmidazolium did not alter TRPM5 activity; (3) adding a calmodulin-binding peptide, the myosin light chain kinase (MLCK) peptide, also failed to exert an effect.

c. PIP2

Many proteins in the plasma membrane exhibit strong sensitivity to PIP2. Multiple lines of evidence support the idea that PIP2 plays a regulatory role for TRPM4. After desensitization, direct application of PIP2 to the membrane patch could partially recover TRPM4 channel current (Figure 4E); application of Mg₂ATP in millimolar concentrations to desensitized channels could also partially revive the current (22, 30, 44). Application of PIP2 to mouse sinoatrial node cells promoted native TRPM4 channel activities (56). It is known that phosphatidylinositol phosphate kinases are stimulated by Mg₂ATP. Consistent with this idea, the potentiation effect of ATP could be obtained only when Mg²⁺ was co-applied with ATP. Wortmannin, a lipid kinase inhibitor, at concentrations that block phosphatidylinositol 4-kinase (PI4K) and phosphatidylinositol 3-kinase (PI3K), inhibited the Mg₂ATP-induced partial current recovery, whereas a PI3K-specific inhibitor LY294002 did not show any inhibitory effect (44). PLC inhibitor U73122 was found to slow down desensitization (31). Furthermore, application of the PIP2 scavenger poly-lysine could speed up desensitization and extend its impact on current amplitude (31, 44). Application of diC8-PIP2, a short-tail, more water-soluble derivative of PIP2, to inside-out patches could at least partially recover the TRPM4 current from desensitization (31, 44). PIP2 shifts voltage-dependent activation towards more negative voltages and dramatically increases the channel’s calcium sensitivity (Figure 4C). These experimental observations establish a link between PIP2 depletion and TRPM4 desensitization, indicating that association of PIP2 with TRPM4 stabilizes its open conformation.

TRPM5 also desensitizes in a PIP2-related manner. Extended application of calcium caused the calcium concentration-dependent activation curve to shift downward and rightward (20). Adding diC8-PIP2 to desensitized TRPM5 channels could enhance current response to calcium. As a result, the calcium concentration dependent activation curve exhibited a large uplift as well as a clear left shift (Figure 4B&C). However, TRPM5 desensitization appears to be a complex process. Desensitization of mammalian TRPM5 channels also exhibits calcium concentration dependence (28).

Locations of the PIP2-binding sites in TRPM4 and TRPM5 have not been found. Mutations of basic residues in the TRP domain of TRPM4 (and of TRPM8 and TRPV5) reduced PIP2 sensitivity and enhanced inhibition by PIP2 depletion (57). The Nilius group found TRP domain mutations did not have a dramatic effect on PIP2-dependent current recovery after desensitization, although the apparent sensitivity to PIP2 was decreased (31). Instead, a cluster of positive charges more distally located in the C-terminus of TRPM4 seemed to exhibit a larger influence on PIP2 binding; mutations of basic residues in this region decreased the apparent affinity for PIP2 and the activity of the channels.

Since many signaling processes affect PIP2 in the plasma membrane, the activity of TRPM4 and TRPM5 may be dynamically regulated as a result. Indeed, desensitization (or sensitization) to repetitive or sustained stimulation is a general feature of many TRP channels, for which PIP2 has been found to play an important role (58). It is therefore important to better understand how PIP2 interacts with these channels.

d. ATP, PKC and polyamine

Perfusing Mg₂ATP to inside-out patches could increase TRPM4’s calcium sensitivity to partially reverse channel desensitization (30, 44), as mentioned earlier. The potentiating effect of Mg₂ATP is thought to be indirect, through activation of a kinase that restores the level of membrane-bound PIP2 (44). In addition, phosphorylation is thought to potentiate TRPM4. It is proposed phosphorylation is mediated by PKC, as treating TRPM4-expression cells with phorbol 12-myristate 13-acetate (PMA) increased the current density (30). PKC was found to also stimulate TRPM4 trafficking and insertion into the plasma membrane, resulting in a boost of channel current (59).

Interestingly, ATP was found to reversibly inhibit TRPM4 current when applied at micromolar concentrations to the intracellular side without Mg²⁺; so did ADP, AMP and AMP-PNP but not GTP, UTP or CTP (21). When the cryo-EM structure of TRPM4 in complex with ATP was solved, ATP was observed to be bound to the lower tier of the intracellular N-terminal domain, between adjacent subunits; a tetrameric channel complex can accommodate four ATP molecules (22). ATP inhibition is therefore likely achieved through an allosteric mechanism. The channel protein interacts with the adenine moiety of ATP via three aromatic residues (H160, W214, and Y228 in the mouse TRPM4) (22), explaining the poor selectivity for channel inhibition among ATP, ADP, and AMP. These residues are not conserved in TRPM5, explaining the observation that ATP does not inhibit TRPM5 (43). The triphosphate group of ATP interacts with arginine residues. Binding of ATP causes a local separation between subunits that can be discerned at the nucleotide binding domain. The intracellular channel structure containing the ATP-binding site moves over a large distance in the open state of TRPM4; it is thought that the bound ATP prevents the activation transition in the pore by disrupting the coupling process (26).

Intracellular polyamine also inhibits TRPM4 and TRPM5, with an IC₅₀ value in the tens of micromolar range (21, 43). Polyamine inhibits inward rectifier potassium channels by binding inside the pore to block ion permeation (60). It is likely that the same mechanism underlies polyamine inhibition of TRPM4 and TRPM5 channels; this however remains to be experimentally tested.

e. Temperature

Several TRP channels are known for their outstanding heat sensitivity in activation gating, which allows them to play a role in detecting changes in temperature (38, 61, 62). Sensitivity of TRPM4 and TRPM5 activation to temperature has been noticed. Their Q₁₀ values, measured from current amplitude changes between 15°C and 35°C, are around 10 (63). It is thought that the sensitivity of TRPM5 activation gating to temperature plays a role in sensory physiology, allowing a better appreciation of the sweet taste (63). The structural underpinning for TRPM4’s temperature sensitivity has been recently revealed (26). It was found that the intracellular domain of TRPM4 resides in drastically different conformations at below room temperature and at 37°C. In the cryo-EM structure obtained from samples first heated to 37°C, the lower part of the channel pore, a.k.a. the neck of the second hourglass, was seen to be wider, likely representing an open state.

6. TRPM4 and TRPM5 pharmacology

The available pharmacological tools for TRPM4 and TRPM5 have been lacking for a long time, which limited biophysical and physiological investigations. Most of the reported modulators lack specificity or high efficacy. The situation however is improving, as the obvious pharmaceutical opportunities these ion channels present attract research activities in both academia and industry looking for effective natural or synthesized molecules. One can anticipate that these activities will yield highly efficacious and selective agonists and antagonists in the very near future. Here we review briefly what pharmacological tools are currently available (Table 1).

Table 1.

TRPM4 modulators

Molecule	EC₅₀/IC₅₀ (μM)	References
Activator / Potentiator
Intracellular Ca²⁺	0.3–1000	Colquhoun, 1981; Yellen, 1982; Launay, 2002; Nilius, 2003; Nilius, 2004; Nilius, 2005; Ullrich, 2005; Yarishkin, 2008; Sala-Rabanal, 2012; Amarouch, 2013; Yamaguchi, 2014; Winkler, 2017; Autzen, 2018; Hu, 2024
Intracellular Co²⁺ with Ca²⁺	107	Yamaguchi, 2014
Intracellular Mn²⁺ with Ca²⁺	ND	Yamaguchi, 2014
Intracellular Ni²⁺ with Ca²⁺	ND	Yamaguchi, 2014
PIP2 with Ca²⁺	4–42.2	Zhang, 2005; Nilius, 2006; Yamaguchi, 2014; Guo, 2017
BTP2	0.008	Takezawa, 2006
Decavanadate with Ca²⁺	1.9	Nilius, 2004; Winkler, 2017; Hu, 2024
Mg₂ATP	ND	Zhang, 2005; Nilius, 2006; Guo, 2017
Inhibitor
Adenosine	630	Sturgess, 1986; Nilius, 2004
AMP	19	Sturgess, 1986; Nilius, 2004
ADP	2.2	Sturgess, 1986; Nilius, 2004
ATP	0.8–2.3	Sturgess, 1986; Nilius, 2004; Guo, 2017; Arullampalam 2021; Hu, 2024
AMP-PNP	19	Thorn, 1992; Nilius, 2004
Spermine	61	Nilius, 2004
Flufenamic acid	2.8–5.5	Korbmacher, 1995; Guinamard, 2006; Demion, 2007; Morita, 2007
Clotrimazole	ND	Ullrich, 2005
Glibenclamide	ND	Guinamard, 2006; Demion, 2007; Sala-Rabanal, 2012
9-phenanthrol	10–30	Grand, 2008; Gonzales, 2010
CBA (Compound 5)	0.7–1.8	Ozhathil, 2018
NBA (Compound 6)	0.1–0.2	Ozhathil, 2018; Arullampalam, 2021

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ND, not determined.

Intracellular calcium remains to be the only known physiological activator for TRPM4 and TRPM5. Its known pharmacological properties and binding sites have been discussed in Section 4. Several molecules are found to potentiate TRPM4 and/or TRPM5 activities. Both PIP2 and Mg₂ATP are discussed previously. A highly negatively charged vanadate oligomer, decavanadate, also mentioned earlier, was found to potentiate TRPM4 activities. BTP2, a 3,5-Bis(trifluoromethyl)pyrazole derivative and an inhibitor of CRAC channels, was found to potentiate TRPM4 (64). While many divalent cations were found to be either ineffective or inhibitory of the TRPM4 current, Co²⁺, Mn²⁺ and Ni²⁺ applied intracellularly exhibited a potentiation effect but only in the presence of intracellular Ca²⁺ (55). Arachidonic acid, a polyunsaturated omega-6 fatty acid precursor for leukotrienes, prostaglandins, and thromboxanes, was reported to potentiate TRPM5 currents when applied from the extracellular side (65).

Adenosine and it phosphate derivatives such as ATP, ADP, AMP, AMP-PNP are all found to inhibit TRPM4, so did polyamines such as spermine (21), as discussed earlier. Flufenamic acid and chlotrimazole are non-specific inhibitors for TRPM4 and TRPM5, apparently by modifying their gating activities (43, 56). Flufenamic acid, which inhibits TRPM4 with an IC₅₀ of 3-to-6 micromole, also affects many other channels including GABA_A and CLC-1 (66). A hydroxyl derivative of the tricyclic compound phenanthrene, 9-phenanthrol, was identified as a TRPM4 inhibitor; it selects TRPM4 over TRPM5 and other TRP channels such as TRPC3, TRPC6, TRPM7 (67). The 9-phenanthrol compound is structurally similar to MPB-104 (5-butyl-7-chloro-6-hydroxybenzo[c]-quinolizinium chloride) that inhibits TRPM4 with an IC₅₀ of 20 micromole but also activates CFTR (67). Still, 9-phenanthrol was found to activate the intermediate conductance calcium-activated potassium channel at the low micromolar range (68) and inhibit several potassium channels (69). Several more favorable TRPM4 inhibitory compounds were developed based on 9-phenanthrol, among them CBA and NBA have gained popularity (70). They exhibited better efficacy than 9-phenanthrol; CBA appeared to exhibit some species preferences, inhibiting only human TRPM4 but not mouse TRPM4, whereas NBA inhibited both human and mouse TRPM4 channels (71). Extracellular protons inhibit TRPM5 through two mechanisms: they promote channel inactivation and block current through the open channel (49). Extracellular zinc ions also inhibit TRPM5, by binding to the pore loop (72). N’-(3,4-dimethoxybenzylidene)-2-(naphthalen-1-yl)acetohydrazide (NDNA) inhibits TRPM5 by binding between the S1-S4 domain and the pore domain (27).

Following an observation that the intracellular ATP regulated swelling of rat brain astrocytes (73), the Simard group proposed that the effect was carried out by ATP inhibition of the sulfonylurea receptor type 1 (SUR1) that associates with TRPM4 (74). This would allow sulfonylurea drugs like glibenclamide and tolbutamide to regulate TRPM4 activity through competitive binding to SUR1 (73). Glibenclamide, an antidiabetic medication, binds to ATP binding cassette (ABC) proteins such as CFTR and SUR1. It was found to strongly inhibit TRPM4 currents at the 10-to-100 micromolar range; however, as expected, it also affects ABC proteins such as CFTR, and K_ATP channels due to its association with SUR1 (56). Direct association of SUR1 and TRPM4 in COS and HEK cells was reported based on evidence from co-immunoprecipitation and fluorescence resonance energy transfer (FRET) (75). The Simard group further reported that aquaporin AQP4 forms a heteromultimeric complex with TRPM4 and SUR1, hence potentially linking calcium signaling to water transport and osmotic regulation (76). However, the Nichols group reported that, at least in COS cells, there was no detectable evidence that over-expressed SUR1 and TRPM4 associated or directly interacted (77). They also failed to observe an inhibitory effect of glibenclamide or tolbutamide after the exogenously expressed TRPM4 channels went through spontaneous desensitization. It is unclear what might have caused the discrepancy. No TRPM4/SUR1 complex structure has been reported.

7. Tissue and organ distribution

The distribution of calcium-sensing TRPM4 and TRPM5 channels among tissues and organs carries important information on their potential functional contributions to physiology. Indeed, conversion of intracellular calcium signaling to changes in membrane potential may powerfully impact cellular function. It is therefore anticipated that functional expression of TRPM4 and TRPM5 would have a substantial contribution to the physiological roles of its host cells. The human disease-causing gain-of-function and loss-of-function TRPM4 mutations, to be discussed later in Section 9, offer supportive cases for this view. A general observation from the published studies so far is that TRPM4 has a broad distribution among tissues and cell types; in comparison, TRPM5 has a more restricted expression pattern. The wide distribution of TRPM4 and TRPM5 channels is consistent with observations on the CAN channels from the pre-cloning age.

The distribution of TRPM4 and TRPM5 has been investigated at the mRNA and protein levels, using PCR, Northern blot, Western blot (WB), immunocytochemistry (ICC), and immunofluorescence (IF) staining of tissue samples. Distribution of GFP-tagged proteins among tissues in transgenic animals was also documented. These methods have different specificities and sensitivities. Results from different studies are sometimes not consistent, which presents challenges to come up with an integrated picture. Functional confirmation of native TRPM4 and TRPM5 channel expression using patch-clamp recordings would offer evidence from a different angle and indeed has been used in many studies. However, the lack of highly selective and effective activators and inhibitors presents limitations. It is therefore likely that the issue of native expression will be revisited in future studies of TRPM4 and TRPM5 in certain tissues or organs. In this section, we give a brief overview of the native expression of TRPM4 and TRPM5 in noticeable organs and tissues. Specific observations will be discussed in the next section when individual physiological functions are examined.

TRPM4: When the short (TRPM4a) and long (TRPM4b) versions of the channel were first discovered, it was noticed that mRNAs encoding them could be detected in a variety of organs, including heart, kidney, liver, pancreas, placenta, skeletal muscle, thymus, spleen, prostate, colon but was absent in leukocytes (12, 13). Subsequently, many studies investigated the expression pattern of TRPM4. For systematic surveys, the McNulty group at GlaxoSmithKline conducted a study of TRPM4 (and other TRPM channels) using PCR (78), and the Oh group at Seoul National University conducted a comparative study of the mRNA levels of TRPM4 (and all other TRP channels) in different tissues (79). Results from these studies confirmed the widespread expression pattern, which is substantiated by a large body of studies in specific tissues or organs (see Table 2 and Figure 5). It should be noted that, when various reports are examined, there could be differences in details such as the relative signal intensities among tissue and organ types.

Table 2.

TRPM4 expression in mammalian species

Organ/Tissue	Species	References	Methods
Cardiovascular system
heart	human	Launay, 2002, Fonfria, 2006; Kruse, 2009; Dragun, 2019; Frede, 2020; Feng, 2021	RT-PCR, qPCR, Northern blot, WB, ICC, IHC, IF, patch clamp
	rat	Guinamard, 2006; Teruyama, 2011; Piao, 2015; Son, 2016; Frede, 2020
	mouse	Demion, 2007; Jang, 2012; Simard, 2012; Kecskés, 2015; Gueffier, 2017; Medert, 2020; Frede, 2020; Guo, 2021; Hedon, 2021; Medert, 2021; Arullampalam, 2023
	dog	Dienes, 2021
	rabbit	Hof, 2016
blood vessel	human	Thilo, 2011; Echeverría, 2015
	rat	Earley, 2004; Yang, 2006; Gerzanich, 2009; Crnich, 2010; Li, 2014; Ding, 2017; Gong, 2019; Csipo, 2022
	mouse	Ali, 2021; Yamasaki, 2023
Immune system
bone marrow	human	Fonfria, 2006	qPCR, Northern blot, IHC, IP, WB, patch clamp
spleen		Launay, 2002; Fonfria, 2006
thymus		Launay, 2002; Launay, 2004
blood mononuclear cell		Fonfria, 2006; Serafini, 2012; Malhotra, 2013; Morita, 2020; Wang, 2020; Çakir, 2021; Ozcan, 2021
macrophage		Fonfria, 2006
T cell	mouse	Launay, 2004; Vennekens, 2007; Weber, 2010
mast cell	mouse	Vennekens, 2007
macrophage		Serafini, 2012
dendritic cell		Barbet, 2008
Nervous system
cerebrum	human	Fonfria, 2006; Schattling, 2012; Tosun, 2013; Mehta, 2015; Hristov, 2016	RT-PCR, qPCR, WB, ICC, IHC, IF, IP, in situ hybridization, FRET, patch clamp
	rat	Li, 2010; Teruyama, 2011; Tosun, 2013; Huang, 2015; Huang, 2016; Chen, 2019; Ma, 2023
	mouse	Crowder, 2007; Jang, 2012; Schattling, 2012; Riquelme, 2018; Yan, 2020; Riquelme, 2021
cerebellum	mouse	Kim, 2013
brainstem	rat	Koizumi, 2018
brainstem	mouse	Koizumi, 2018; Li, 2021
pituitary	human	Fonfria, 2006
spinal cord	human	Schattling, 2012
	rat	Woo, 2013; Turtle, 2019
	mouse	Schattling, 2012; Vandewauw, 2013; Bianchi, 2018; Yao, 2018; Tsymbalyuk, 2021
Urogenital system
bladder	human	Hristov, 2016	RT-PCR, qPCR, Northern blot, WB, ICC, IHC, IF, patch clamp
	rat	Smith, 2013a
	mouse	Yu, 2011; Kullmann, 2018
	guinea pig	Smith, 2013b; Maxwell, 2021
kidney	human	Launay, 2002; Fonfria, 2006
	rat	Teruyama, 2011; Dusmez, 2014; Piao, 2015
	mouse	Jang, 2012
placenta	human	Launay, 2002; Fonfria, 2006
uterus	human	Fonfria, 2006; De Clercq, 2015; Persoons, 2018
uterus	mouse	De Clercq, 2017
prostate	human	Fonfria, 2006; Hristov, 2016
prostate	rat	Wang, 2007
testis	rat	Li, 2010; Jang, 2012
Respiratory system
lung	human	Fonfria, 2006	RT-PCR, qPCR, IHC
	rat	Piao, 2015
	mouse	Jang, 2012
Digestive system
liver	human	Launay, 2002; Fonfria, 2006	RT-PCR, qPCR, Northern blot
liver	rat	Piao, 2015
stomach	human	Fonfria, 2006
intestine	human	Fonfria, 2006
Sensory system
inner ear	mouse	Takumida, 2009; Sukuraba, 2014	RT-PCR, qPCR, WB, IHC, IF, patch clamp
eye	human	Yarishkin, 2022 (trabecular meshwork cells)
eye	mouse	Choi, 2015 (optic nerve head)
tongue	rat	Teruyama, 2011
Others
pancreas	human	Launay, 2002; Fonfria, 2006; Marigo, 2009	RT-PCR, qPCR, Northern blot, WB, IP, ICC, IHC, patch clamp
	rat	Cheng, 2007; Marigo, 2009; Piao, 2015, Ma, 2017
	mouse	Marigo, 2009; Nelson, 2011; Diszházi, 2021
	hamster	Marigo, 2009
skin	human	Fonfria, 2006; Vennekens, 2007; Wang 2019; Otsuka Saito, 2023	RT-PCR, qPCR, Northern blot, WB, patch clamp
skeletal muscle	human	Launay, 2002
skeletal muscle	mouse	Krüger, 2008
breast	human	Wong, 2020
stem cell	human	Tran, 2014
stem cell	rat	Nelson, 2013
adipose	human	Fonfria, 2006; Tran, 2014

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Figure 5. — Summary of reported TRPM4 distribution in human (A) and rodents (B). The color scale indicates relative levels of expression based on consensus of reports in the literature. The colored circles depict TRPM4-expressing specific cells, tissues or organs in humans.

TRPM5: In contrast to the broad expression pattern of TRPM4, expression of TRPM5 appears to be restricted to specific cell types, as summarized in Table 3 and Figure 6. A systematic survey of TRPM5 expression of juvenile and adult mice using a reporter mouse model is consistent with this view (80). Substantial attention has been focused on the effector role of TRPM5 in chemical sensing. Accordingly, there is a much-detailed understanding of TRPM5 distribution in sensory cells. Nonetheless, expression of TRPM5 in other cell types has been widely reported.

Table 3.

TRPM5 expression in mammal species

Organ/Tissue	Species	References	Methods
Taste tissue
tongue	monkey	Gonda, 2013	RT-PCR, qPCR, Northern blot, in situ hybridization, IF, WB, TRPM5-GFP mice, patch clamp
	rat	Teruyama, 2011; Padalhin, 2022
	mouse	Pérez, 2002; Pérez, 2003; Zhang, 2003; Clapp, 2006; Kaske, 2007; Zhang, 2007; Liu, 2011; Herrera Moro Chao, 2016; Cui, 2019; Wu, 2020; Nguyen, 2021
	chicken	Yoshida, 2017
palate	chicken	Yoshida, 2017
Olfactory system
main olfactory epithelium	mouse	Kaske, 2007; Lin, 2007; Lin, 2008b; Nakashimo, 2010; Oshimoto, 2013; López, 2014; Yamaguchi, 2014; Fu, 2018; Genovese, 2018; Lemons, 2020; Dnate Baxter, 2021	in situ hybridization, IHC, IF, TRPM5-GFP mice, patch clamp
GI tract
oesophagus	human	Young, 2008	RT-PCR, qPCR, IHC, IF, Northern blot, in situ hybridization, WB, TRPM5-eGFP mice
stomach	human	Young, 2008; Widmayer, 2012
	monkey	Gonda, 2013
	mouse	Pérez, 2002, Pérez, 2003; Kaske, 2007; Cui, 2019
intestine	human	Fonfria, 2006; Young, 2008
	monkey	Gonda, 2013
	rat	Feng, 2017; Kang, 2020
	mouse	Pérez, 2002; Pérez, 2003; Kaske, 2007; Bezençon, 2008; Young, 2008; Kokrashvili, 2009; Herrera Moro Chao, 2016; Howitt, 2016; Cui, 2019; Zheng, 2023
Respiratory system
lung	mouse	Herrera Moro Chao, 2016	RT-PCR, qPCR, IHC, IF, TRPM5-GFP mice, patch clamp
trachea	rat	Kaske, 2007
trachea	mouse	Kaske, 2007; Herrera Moro Chao, 2016; Genovese, 2018
bronchus	mouse	Kaske, 2007
nose	human	Barham, 2013
nose	mouse	Kaske, 2007; Lin, 2008a
Brain
third ventricle	mouse	Yu, 2023	RT-PCR, qPCR, ICC, IHC, IF, TRPM5-GFP mice
hippocampus	mouse	Herrera Moro Chao, 2016
cortex	mouse	Herrera Moro Chao, 2016
hypothalamus	rat	Teruyama, 2011
hypothalamus	mouse	Herrera Moro Chao, 2016
amygdala	mouse	Thompson, 2012
cerebellum	mouse	Kim, 2013
brainstem	mouse	Crowder, 2007; Herrera Moro Chao, 2016
pituitary	human	Fonfria, 2006
Others
pancreas	human	Fonfria, 2006	RT-PCR, qPCR, WB, IF, patch clamp
	rat	Prawitt, 2003
	mouse	Colsoul, 2010; Colsoul, 2014
heart	rat	Teruyama, 2011
kidney	human	Fonfria, 2006
	rat	Liu, 2011; Teruyama, 2011
	mouse	Crowder, 2007; Cui, 2019
prostate	human	Fonfria, 2006
skin	human	Mardaryev, 2021
odontoblast	mouse	Khatibi Shahidi, 2015

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Figure 6. — Summary of reported TRPM5 distribution in human (A) and rodents (B). The color scale indicates relative levels of expression based on consensus of reports in the literature. The colored circles depict TRPM4-expressing specific cells, tissues or organs in humans.

8. Potential functional roles in physiology

TRPM4 and TRPM5 have been implicated in a variety of physiological processes. In general terms, activities of TRPM4 and TRPM5 influence physiology in two ways—by depolarizing the plasma membrane and by its feedback control on calcium signaling. Membrane depolarization is the direct effect. This contribution is better appreciated in excitable cells such as cardiomyocytes, immune cells, pancreatic beta cells, and neuronal cells such as taste cells. Given their comparable permeability to Na⁺ and K⁺, the reversal potential of currents mediated by TRPM4 and TRPM5 is close to zero mV. For an excitable cell that typically has a deeply negative resting membrane potential, TRPM4 or TRPM5 activities would have a strong depolarizing effect. It may help elevate membrane potential to increase excitability and, upon reaching the threshold, trigger action potential firing; they may also contribute to extending the duration of action potentials. However, most excitable cells express a collection of excitatory ion channels, many of which can be sensitive to calcium. The challenge in determining whether and to what extent TRPM4 or TRPM5 participates in the cellular physiology of a particular cell type lies in the ability (or the lack of) in quantifying their relative contribution to membrane depolarization. The lack of highly selective pharmacological tools for these channels contributes to this challenge.

The second way TRPM4 and TRPM5 contribute to cellular physiology is by feeding back on the intracellular calcium signaling that activates them (Figure 7). For cells expressing voltage-gated Cav channels, membrane depolarization due to TRPM4 or TRPM5 activation may activate these highly calcium permeable channels, leading to a dramatic increase in calcium influx. This is a positive feedback process and has the potential to quickly bring the intracellular calcium concentration to a high level to promote calcium-dependent events. (Note that activities of TRPM4 and TRPM5 also exhibit a weak voltage sensitivity—see Section 5a—which provides an intrinsic positive feedback mechanism.) For cells expressing voltage-insensitive calcium-permeable ion channels such as CRAC channels, for example, many non-excitable cell types, the effect of TRPM4 or TRPM5 activation would be the opposite. Membrane depolarization would reduce the electrical driving force for calcium influx; the effect is expected to be more prominent in cells having a weakly negative resting membrane potential. This is a negative feedback process leading to a drop of the intracellular calcium concentration. An additional challenge in determining the feedback role of TRPM4 and TRPM5 is the fact that most calcium-permeable ion channels are themselves sensitive to the intracellular calcium level. The ability to distinguish contributions by these channels from that by TRPM4 or TRPM5 would be crucial in assessing the potential role of the latter to cellular physiology.

Figure 7. — Positive (left side) and negative (right side) feedback regulation of calcium signaling by TRPM4. Solid red arrows indicate calcium flow; dash red arrows indicate calcium regulation targets. Solid black and deep blue arrows indicate sodium and potassium flow, respectively. CRAC, calcium release-activated calcium channel; STIM, stromal-interaction molecule; ER, endoplasmic reticulum.

As mentioned above, one limitation in deciphering the physiological functions of TRPM4 and TRPM5 is the lack of selective pharmacological tools to activate or inhibit them. The following cases illustrate this point well. The TRPM4 inhibitory compound 9-phenanthrol (81) has been widely used in published studies. In one study focusing on the mast cells, treatment with 9-phenanthrol was found to indeed induced mast cell degranulation (82). However, the effect did not seem to depend on TRPM4 but instead might be due to an off-target effect of 9-phenanthrol activating K_Ca3.1. The reagent, while sparing TRPM5 (67), also inhibits TMEM16A channels (83). It was further observed that 9-phenanthrol and other known TRPM4 inhibitors exhibit species and application dependent effects (71). These examples highlight the pressing need for better pharmacological tools for the study of TRPM4 and TRPM5 (70), and underscore the need to use caution in interpreting functional data. As new pharmacological tools with better efficacy and specificity are emerging (84), one can be optimistic that our ability to assess the physiological roles of TRPM4 and TRPM5 will be much improved in the near future.

In the following sections, we overview major working hypotheses on the physiological functions of TRPM4 and TRPM5.

a. TRPM4 in the cardiovascular system

The heart is a calcium-driven pump whose rhythm is controlled by electrical signals (Figure 8). The vasculature tone is also dynamically regulated by calcium and membrane potential. TRPM4, with its ability to link calcium and electrical signaling, is well-equipped to exert an influence on the cardiovascular system. Several lines of evidence strongly argue for a role of TRPM4 in the cardiovascular system. (i) TRPM4 expression in various parts of the heart and in vasculature has been detected in many labs (Figure 5). (ii) The observed expression pattern is consistent with earlier observations of CAN channels in these tissues (see Section 2). (iii) A long list of gain-of-function and loss-of-function TRPM4 mutations are linked to human hereditary heart diseases such as the long QT syndrome and the Brugada syndrome. (iv) The TRPM4 inhibitor 9-phenanthol exhibited protective effects for ischemia heart (85, 86) and reduced the action potential duration in Purkinje fibers (87). (v) TRPM4 knock-out mice exhibited elevated or reduced cardiac hypertrophy under stress conditions (88–90).

How would TRPM4 contribute to heart physiology? With each heartbeat cycle, there is a dynamic wave of intracellular free calcium increase and decrease. The opportunity to convert a transient increase in calcium concentration into membrane depolarization has clear and attractive utilities in the heart and the vasculature (as well as other tissues such as the nervous system). One possible role of TRPM4 is to shape the pacemaker potential, a spontaneous diastolic depolarization of the sino-atrial cells. The depolarizing pacemaker current is mediated by a number of ion channels and transporters including the hyperpolarization-activated cyclic nucleotide-gated channel HCN4 (of the voltage clock) and Na⁺/Ca²⁺ exchanger NCX (of the calcium clock) (91). A component of the pacemaker current is mediated by calcium influx. While NCX activity is electrogenic and sensitive to calcium, replacing sodium with the NCX-impermanent ions K⁺ or Li⁺ did not eliminate the calcium-sensitive component (92, 93). As further evidence, 9-phenathrol reduced the beating rate with a half-maximal inhibition concentration comparable to that of TRPM4 and only in wildtype mice but not TRPM4 knockout mice (94). Another possibility is that TRPM4 activity contributes to the plateau phase of a cardiac action potential (though the TRPM4 current is expected to be small when the membrane potential is close to its reversal potential at near zero mV). If so, one can imagine that enhancing it could lead to a longer QT interval and disruption to other aspects of the cardiac electrical activity as seen in patients carrying one of the TRPM4 gain-of-function mutations; on the flip side, reducing TRPM4 activity over time may lead to hypertrophy of the heart as seen in the animal models—indeed, 9-phenathrol application reduced atrial action potential duration in the wildtype but not TRPM4 knockout mice (95). The heart electrical activity is so delicately controlled, it does not require a robust current to alter it to an extent that exhibits physiological and pathological consequences.

Of various human organs, the heart is one of the most noticeable for TRPM4 expression. Besides those mentioned earlier, the Pongs group observed that, among heart tissues, the highest level of TRPM4 mRNA was found in Purkinje fibers, followed by septum and right ventricle (96). In other studies of the human heart, TRPM4 mRNA was detected in the left ventricle (97); TRPM4 protein was detected in right ventricle (98) and left ventricle (99). Patch-clamp recordings identified currents with TRPM4 characteristics from the left ventricular fibroblasts (99). In addition, TRPM4 mRNA was detected in the cerebral vascular tissues (100); TRPM4 protein was detected in umbilical vein endothelial cells (101).

Findings from animal studies lend support for the conclusion that TRPM4 expresses broadly in the cardiovascular system. A survey of mRNA presence found messengers for TRPM4, among several TRPM and TRPV channels, in rat pulmonary arteries and aorta (102). Detection of TRPM4 protein in rat ventricular myocytes is consistent with functional data indicating that the TRPM4 inhibitor 9-phenanthrol preserved cardiac contractile function and protected the heart from ischemia reperfusion damage (85, 86). Both mRNA and protein were detected from mouse sino-atrial node cells; patch-clamp recordings confirmed the presence of a current with TRPM4 channel characteristics (56). A comparative study in mice suggested the highest levels of TRPM4 mRNA in lung and testis though it was positively detected the heart (79). Interestingly, 9-phenanthrol was found to be ineffective in reducing action potential duration in rabbit ventricle, though the same treatment was effective in Purkinje fibers (87). Selective deletion of TRPM4 from the mouse heart was linked to cardiac hypertrophy after chronic angiotensin treatment (103); similarly, TRPM4 knock-out (KO) mice developed cardiac hypertrophy during endurance training (104). Curiously, the TRPM4 expression level in the ventricle was found to be reduced in a monocrotaline-induced pressure load rat model (98) but increased in a spontaneously hypertensive rat model (105). It was also observed that selective deletion of TRPM4 in mouse cardiomyocytes led to a reduction in the left ventricular hypertrophy (89); in vitro experiments suggested that activation of TRPM4 in atrial myocytes can be regulated by the mechanosensitive Piezo1 channels (106). Results from additional knock-out studies further support a dynamic functional role of TRPM4 in the heart (90, 107–109).

Beyond the heart, TRPM4 is found to also contribute to the regulation of vascular tone (Figure 9). Myogenic constriction of arteries and arterioles is regulated by intracellular calcium. While potassium and chloride channels are known to contribute to the regulation of membrane potential that controls the Cav channel activity (110), TRPM4 is well-posed to amplify vascular responses. Indeed, a stretch-activated cation channel resembling TRPM4 was observed (111). TRPM4 in smooth muscles indeed can have a major role in myogenic constriction of the cerebral arteries, consistent with the presence of TRPM4 (but not TRPM5) mRNA and single-channel currents with properties resembling those of TRPM4 (112, 113). Interestingly, it appears that activation of TRPM4 channels in cerebral artery myocytes is not regulated by calcium entry from Cav channels but likely from calcium released from the intracellular store sarcoplasmic reticulum (114). An additional, more global regulatory mechanism than that shown in Figure 8 was identified, involving dynamic membrane trafficking of TRPM4 channels (59, 115). It was found that reduced TRPM4 activity is linked to the Gould syndrome (116), and inhibiting TRPM4 activity by nitric oxide causes blood vessel dilation (117). Simulations suggest that overexpression of TRPM4 (as seen in conduction block patients with gain-of-function TRPM4 mutants) may lead to propagation failure (118).

In support of a role TRPM4 plays in vasculature, it was shown that suppression of TRPM4 expression or function reduced myogenic tone and induced vasoconstriction of rat cerebral parenchymal arterioles (119). Channels with TRPM4 characteristics were detected in freshly isolated rat vascular smooth muscle cells, lending functional supports to findings of TRPM4 (and TRPM5) mRNA in these cells (112). Additional studies found TRPM4 expression in rat mesenteric artery endothelial cells (120, 121), rat cerebral artery myocytes (117, 122), and mouse cerebral arteries (116). Suppressing TRPM4 expression with antisense oligodeoxynucleotides eliminated pressure-induced membrane depolarization and stimulated arterial constriction (112). In another study, the basal level of TRPM4 expression in rat capillaries was found to be low but was abundantly upregulated following spinal cord injury, which was linked to the severity of the induced secondary hemorrhage (123).

Nonetheless, there are arguments against a substantial role of TRPM4 in the cardiovascular system under physiological conditions. Indeed, the heart harbors a long list of ion channels whose symphonious activities drive rhythmic heart beating during the life span of the heart (Figure 8). While most of these channels are well-characterized (91), evidence for TRPM4 activity in the heart is relatively weak, leading to concerns on whether it has a substantial contribution to normal cardiac electrophysiology. One can point to Cav channels, SK channels, calcium-activated chloride channels, and NCX in the heart when looking for a linkage between intracellular calcium signaling and membrane depolarization (though they exhibit clear differences in functional properties from TRPM4). Even the strong linkage between gain-of-function TRPM4 mutations and hereditary heart diseases could be interpreted as a gained phenotype produced by an abnormally amplified TRPM4 current. Observations using 9-phenanthol might arise from its off-target effect, so do systemic Trpm4 knock-out. Most of the cardiac phenotypes of TRPM4 knock-out mice were not obvious unless the mice were put through various stresses. On top of these concerns is the high calcium concentrations required to activate TRPM4 in the majority of existing reports. However, none of these concerns appear to be sufficiently strong to confidently rule out a role TRPM4 plays in the cardiovascular system. For example, the experimentally observed high calcium activation concentrations could be the result of channel desensitization or the lack of co-factor(s) in expression systems (124).

b. TRPM4 in the immune system

During an immune response, long-lasting oscillation of the intracellular calcium concentration is associated with T cell activation (125, 126). Membrane potential serves a critical regulatory role for calcium entry across the plasma membrane, by providing the electrical driving force for ion influx (e.g., through CRAC channels) instead of directly controlling voltage-gated calcium channels (127, 128) (Figure 10). Both voltage-gated potassium channels (Kv1.3) and calcium-activated potassium channels (KCa3.1 and KCa2.2) are known to contribute to membrane potential regulation in T cells (128). However, being potassium-permeating ion channels, their activities would hyperpolarize the membrane potential. Also present in T cells are chloride-permeable channels (LRRC8), which are likely the most abundant among T cell ion channels. LRRC8 is activated by a decrease in ionic strength and the subsequent cell swelling. Like the currents mediated by potassium channels, the LRRC8 current is hyperpolarizing. Activation of TRPM4 by calcium, in contrast, would elevate membrane potential, reducing the electrical driving force for calcium entry through the Orai1/STIM1 CRAC channels. In this way, it may provide a negative feedback mechanism to limit calcium entry, acting as a rapid break to keep calcium entry in check. T cell activation is driven by the tyrosine kinase/phospholipase C pathway, which breaks down PIP2 to produce the signaling molecule IP3 to trigger calcium release from IP3 receptors. Since PIP2 binding to TRPM4 is required for channel activation, removal of PIP2 from the plasma membrane has the parallel effect of downregulating TRPM4 activity to allow Kv and KCa channels to hyperpolarize the cell. In support of the working hypothesis that TRPM4 contributes to an immune response, inhibiting TRPM4 activity led to a sustained elevation of T cell intracellular calcium concentration and enhanced interleukin-2 production (32). Similar observations were made in T helper cells, in which small interference RNA suppression of TRPM4 expression increased calcium influx and the oscillatory level in Th2 cells, and decreased influx and oscillations in Th1 cells (129). This cell-type dependence may be related to the relatively higher expression of TRPM4 in Th2 cells compared to Th1 cells.

Figure 10. — Physiological function of TRPM4 in T cells. Solid red arrows indicate calcium flow; dash arrows indicate calcium regulation targets. Solid black and deep blue arrows indicate sodium and potassium flow, respectively. Only selected ion channels are shown. CRAC, calcium release-activated calcium channel; CaM, calmodulin; p-MHC, peptide presented by major histocompatibility complex; CD4, cluster of differentiation 4; TCR, T-cell receptor; TK, tyrosine kinase; PLCγ, phosphoinositide phospholipase C γ subunit; IL-2, interleukin-2; ER, endoplasmic reticulum.

In support of the role of TRPM4 in the immune system, TRPM4 mRNA was detected in spleen, thymus, and cell-line cells for monocytes (U937), B lymphocytes (Ramos), T lymphocytes (Jurkat) (13, 78) but not in leukocytes when they were examined as a whole (12). A survey for TRP channels in peripheral blood mononuclear cells from psoriasis patients identified a decrease in the TRPM4 mRNA level (130). TRPM4 protein expression was detected by antibody in thymocytes, D10.G4, Molt-4 and Jurkat cells (32), and in mouse dendritic cells (131). Both TRPM4 mRNA and protein were identified from bone marrow-derived mast cells and CD3⁺CD4⁺ T cells but not CD3⁺CD8⁺ T cells or CD19⁺ B cells; no expression of TRPM5 in these cells was detected (132). Two studies provided strong evidence for functional TRPM4 expression in human and murine T cells using PCR and WB/immunoprecipitation (IP) combined with calcium imaging or patch-clamp techniques; both studies found that inhibition of TRPM4 expression increases Ca²⁺ influx in T cells (32, 129). The Weber et al. study further found that TRPM4 mRNA has a higher expression level in Th2 cells than Th1 cells; inhibition of TRPM4 expression in Th2 and Th1 cells exhibited opposite effects on the basal Ca²⁺ level and oscillation, indicating that different expression levels of TRPM4 in the two types of T helper cells play a distinct role in T cell function by differentially regulating Ca²⁺ signaling (129). Besides T cells, high levels of TRPM4 mRNA and protein have been reported in mast cells derived from bone marrow and skin. For example, based on the differences in current amplitude in Trpm4^+/+ and Trpm4^−/− mice bone marrow-derived mast cells (BMMCs), it has been suggested that TRPM4 expression in mast cells contributes at least partially to the endogenous CAN current; indeed, Trpm4^−/− BMMCs had more Ca²⁺ entry compared to Trpm4^+/+ BMMCs after FcεRI stimulation (132). Collectively, these findings indicate a critical role TRPM4 plays in immune system. Recently, several studies were conducted to test TRPM4 mRNA expression in peripheral blood mononuclear cells of patients with various diseases including multiple sclerosis, psoriasis, as well as inflammatory bowel disease; most of them however did not observe any significant change of TRPM4 expression compared to the control group except for one study of psoriasis patients (133–135). Given the cell-type dependence mentioned above (129), information from cell-type specific analyses is needed.

c. TRPM4 in Skin Health

It was reported that a hereditary TRPM4 mutation (I1040T) and a sporadic mutation (I1033M), both gain-of-function in nature, are linked to a severe form of skin disease named progressive symmetric erythrokeratodermia (PSEK) (136). Both mutant channels exhibited higher basal activities and increased sensitivity to calcium; HEK cells overexpressing them had an elevated resting membrane potential. The finding of skin disease-liked mutations highlights a potential role of TRPM4 in skin health. This is consistent with reports of TRPM4 expression in various skin cells (78). A recent study offers supportive evidence for the TRPM4 presence in keratinocytes: besides detecting TRPM4 protein in human keratinocytes and HaCat cells, it was found that BTP2 and aluminum potassium sulfate—both are TRPM4 agonists—could reduce cytokine production induced by tumor necrosis factor alpha in these cells (but not in Trpm4 deficient HaCaT cells) (137). TRPM4 expression was also detected in connective tissue mast cells of the skin (138).

Several lines of evidence in the Wang et al. report point to a potential role of TRPM4 in regulating keratinocyte proliferation and migration (136). HaCaT cell stably overexpressing either of the two mutant TRPM4 channels exhibited enhanced cell viability; EdU-based proliferation assay confirmed a significantly increased percentage of proliferating cells; higher rates of S and G2/M phase cells were identified in the population. Up-regulation of markers for proliferation and differentiation of keratinocytes such as Ki-67 (a nuclear marker for cell proliferation) and keratin 14 (a marker for undifferentiated keratinocytes) was observed in the affected skin tissues. However, the skin is not simply a physical protective barrier; it also serves as an immune organ to fend off pathogens from the ambient environment. It is just as likely that the skin disease PSEK is due to a disturbance to the immune function caused by elevated TRPM4 activities. Indeed, knock-in mice carrying one of the PSEK mutant are predisposed to more severe psoriasiform dermatitis compared to control mice (139). In a recently reported clinical case, the humanized anti-interleukin 36 receptor monoclonal antibody spesolimab was successfully used in treating a generalized pustular psoriasis patient carrying a TRPM4 mutation (140). Psoriasis is an immune disorder caused by immune system overactivity that renders skin cells to multiply too quickly. It remains to be determined whether overactive TRPM4 channels in the keratinocytes or dendritic cells exhibit a dominant role in psoriasis.

d. TRPM4 and TRPM5 in the Nervous system

TRPM4 expression in the nervous system has been widely noticed. Both TRPM4 mRNA and protein were detected in human cortex as well as spinal cord using quantitative real-time PCR (qPCR), in situ hybridization, and immunostaining; importantly, TRPM4 expression was upregulated in active demyelinating white matter brain lesions of individuals with multiple sclerosis in comparison to control samples but without any changes in the neuronal somata of the same samples (141). In rodents, TRPM4 expression was detected in several brain regions, such as cortex, hippocampus, hypothalamus, and spinal cord. TRPM4 was found to couple with NMDA receptors in mouse cortex and hippocampus (142). Furthermore, two recent neuroanatomy studies have characterized the postnatal developmental TRPM4 expression in mouse medial prefrontal cortex and hippocampus using immunostaining and patch-clamp recording (143, 144).

The functional significance of TRPM4 activities in the nervous system is not well understood. In hippocampal neurons, TRPM4 may contribute to postsynaptic depolarization and long-term potentiation (LTP) (144–146). TRPM4’s ability to link membrane potential changes and calcium signaling appears to be important for the control of hormone release from hypothalamic neurosecretory cells (147). TRPM4 channels are found to exhibit important roles in neuronal cell death (148), CA1 pyramidal cell excitability (149), loss of mossy cells from hippocampal dentate gyrus in temporal lobe epilepsy (150). TRPM4 mRNA or protein expression was detected in human trabecular meshwork (TM) cells (151) and murine optic nerve head (152). Functional expression of TRPM4 in the human eye was detected in TM cells using whole-cell and single-channel patch-clamp recordings; it is suggested that interactions between TRPM4 and another TRP channel, TRPV4, play an essential role in emergent temporal signaling in TM cells (151). TRPM4 mRNA and protein levels were found to be upregulated in brain or/and spinal cord in an experimental auto-immune encephalomyelitis (EAE) mouse model (141, 153). The usage of glibenclamide or ablation of Trpm4 gene could reduce the EAE-induced neuronal injury, indicating that TRPM4 is a potential target for EAE treatment (141). Upregulated TRPM4 protein expression was also detected in surrounding rat brain tissue 24 hours after traumatic brain injury (TBI), whereas 9-phenanthrol significantly diminished this upregulation (154). In a rat subarachnoid hemorrhage (SAH) model, it was shown that TRPM4 expression was three-times higher in cortex adjacent to SAH compared to uninjured control (155). In addition, TRPM4 mRNA and protein were upregulated in rat cortex and hippocampus after cardiac arrest, whereas glibencalmide could downregulate the elevated protein level when combined with target temperature management (156, 157).

Like TRPM4, TRPM5 has been suggested by a large body of literature to play a role in the nervous system. Both TRPM4 and TRPM5 were found to be expressed in rat hypothalamus but with different distribution patterns: TRPM4 mainly expressed in cell bodies of vasopressin and oxytocin neurons, whereas TRPM5 was predominantly found in dendrites of vasopressin neurons (158). TRPM5 mRNA expression was observed in many rodent brain regions such as cortex, hippocampus, hypothalamus and brainstem, and was suggested to be involved in energy homeostasis (159). In particular, the brainstem, where TRPM5 mRNA was found to be abundant, exhibited significant downregulation in both obese-hyperglycemic (ob/ob) mice and diet-induced obese mice compared to control group. Expression of GFP-tagged TRPM5 was detected in tanycytes in the third ventricle of mice brain; it is suggested that these tanycytes not only mediate bidirectional communication between the cerebrospinal fluid and blood but also play critical roles in making responses to metabolic hormones like leptin and in activating insulin secretion (160). Additionally, both TRPM4 and TRPM5 mRNA were detected in murine pre-Bötzinger complex of brainstem that regulates inspiratory burst activity, indicating that TRPM4 and TRPM5 may participate in inspiratory burst generation (161). In addition to the above brain regions, TRPM5 mRNA or protein expression has been reported in the mouse amygdala (162) and human pituitary (78). TRPM5 has been found to contribute to electrical activities of the spinal motoneurons (163).

TRPM4 and TRPM5 are also found to be expressed in Purkinje cells from mouse cerebellum, but they were not functionally required for depolarization-induced slow current (164). TRPM4 mRNA and protein were found in rodent respiratory neurons; it is proposed that TRPM4 expressed in pre-Bötzinger complex is important for respiratory pattern formation but is not required for respiratory rhythm generation (165). TRPM4 expression in retrotrapezoid nucleus (RTN) neurons may contribute to pacemaker firing and breathing (166). In addition, several studies have observed TRPM4 protein expression in rodent spinal cord, which was upregulated after spinal cord or peripheral nerve injury (167–170).

e. TRPM5 in the sensory system

Since TRPM5 expression has been detected in relatively limited cell types in comparison to TRPM4, research activities had mostly focused on its potential role in sensory physiology, insulin and endogenous opioids release. Shortly after the cloning of the Trpm5 gene (17, 171) and the detection of high levels of TRPM5 expression in taste cells (172), a gene knockout study revealed its critical role in sensing sweet, bitter and umami tastes (45) (Figure 11). Unlike the sour and salty taste modalities, these three taste modalities are mediated by G-protein coupled receptors T1Rs and T2Rs; downstream signaling involves PLC-catalyzed hydrolysis of PIP2 to produce IP3, which in turn triggers calcium release from intracellular store. Knocking out TRPM5 eliminated sweet and bitter reception (45) and at least dramatically reduced taste reception for umami and nicotine (45, 173, 174). TRPM5 channels (unlike TRPM4 channels) are blocked by extracellular protons at the pH levels of 6.0 or lower (49); this property would make TRPM5 channels unfit for sensing sour taste. TRPM5 knock-out mice would have to develop a preference for sucrose by an alternative pathway (175). TRPM5 appears to be the downstream effector of PLCβ2, which co-expresses with TRPM5 in taste bud sensory neurons and its removal by knock-out exhibited a similar phenotype to knocking out TRPM5 (45); in vitro experiments showed activation of TRPM5 by IP3-induced depletion of intracellular calcium store (172). In TRPM5-expressing taste cells, both IP3 and calcium elicited excitatory currents (176) and ATP release (177). Therefore, TRPM5 current activated by calcium release from intracellular store serves as the effector of taste signal transduction (178). The TRPM5-mediated excitation of taste cells also transduces sensory signaling for fat and carbohydrate (179–181), regulates glucose homeostasis (160), and may contribute to warmth enhancement and bitter suppression of sweet sensation (63, 182). Taken together, these findings indicate that TRPM5 is indispensable in the taste transduction pathway.

Figure 11. — Physiological function of TRPM5 in taste cells. Solid red arrow indicates calcium flow; dash arrow indicates calcium regulation targets. Solid black and deep blue arrows indicate sodium and potassium flow, respectively. Gα, G protein α subunit; ER, endoplasmic reticulum.

In support of a role of TRPM5 in taste sensation, TRPM5 expression in the tongue has been widely noticed. It was reported that TRPM5 expression exhibits a restricted manner with particularly high levels in taste cells, together with the other signal transduction components such as Gγ13, PLCβ2 and inositol 1,4,5-trisphosphate receptor type III (IP3R) (172, 178). This study also showed a noticeable but lower level of TRPM5 expression in the GI system, to be discussed later. TRPM5 was found to co-express with T1R and T2R taste receptors in murine tongue, and deficiency of TRPM5 or PLC- β2 could eliminate sweet, umami and bitter taste perception without affecting sour or salty tastes (45). In Trpm5-GFP mice tongue, voltage-dependent Na⁺ and K⁺ currents could be recorded but not Ca²⁺ currents, consistent with TRPM5 being a CAN channel (183). Moreover, the Liman group also detected the expression of TRPM5 in murine tongue using the Trpm5-GFP mice, and demonstrated that both IP3 and calcium could trigger TRPM5-dependent currents in intact taste cells, but only intracellular calcium could activate TRPM5 in excised patches (176). TRPM5 expression in the tongue was confirmed in several additional studies (159, 184, 185). High TRPM5 expression in chicken palate rather than the tongue was reported (186). TRPM5 was found to abundantly express in mouse tongue epithelium, and ablation of Trpm5 or application of TRPM5 inhibitor caused impaired aversion to high-salt diet and developed salt-induced hypertension (187). In a follow-up study, long-term intake of bitter melon extracts was found to reinforce the aversion to high-salt diet by upregulating TRPM5 expression and function in mice, thereby preventing high-salt induced cardiovascular dysfunction and angiotensin II-induced hypertension (188). TRPM5 channels in murine taste buds may play a role in the linoleic acid transduction pathway (189).

Olfactory transduction, like taste, uses GPCR-mediated signaling but cyclic nucleotide-gated (CNG) channels and calcium-activated chloride channels as sequential effectors. Nonetheless, the PLC-TRPM5 pathway is found to operate in olfactory sensory neurons (OSNs) to transmit reception of semiochemicals, perhaps operating in parallel with the CNG/chloride channels pathway (190). Comparative functional tests with Trpm5-GFP mice, Trpm5 KO mice and SKn-1a KO mice revealed that TRPM5-expressing microvillous cells (MVCs) play important roles not only in maintaining the olfactory function, but also in regulating main olfactory epithelium (MOE) multicellular network activity, region-specific cell proliferation, and apoptosis during chemical exposure MOE (191–193). Knocking out TRPM5 in mice also eliminated the trigeminal response to airborne xenobiotics (194). Microarray data suggest TRPM5-expressing MVCs are likely involved in viral infection of olfactory epithelium (195). It is interesting to notice that calcium entry through CNG channels triggers negative feedback mechanisms to induce desensitization to sustained odor presence; TRPM5 channels on the other hand are activated by calcium. For certain odorants, it might be advantageous to retain long-lasting sensitive detection.

In support of the view that TRPM5 plays critical roles not only in the taste system but also in the olfactory system, there is growing evidence demonstrating strong TRPM5 expression in OSNs and MVCs of murine main olfactory epithelium. It was found that TRPM5 colocalizes with cyclic nucleotide-gated channel CNGA2 subunit and components of the PLC pathway in OSNs; TRPM5-expressing OSNs project axons to glomeruli in the ventral area of the MOE and participate in signal transduction of putative pheromones (190). TRPM5 immunoreactivity was detected in newborn or adult mice OSNs (196–198). However, the expression of TRPM5 mRNA in adult OSNs is controversial. In contrast to the previous studies, it was also reported that TRPM5 mRNA expression could not be detected in adult OSNs but in adult MVCs and embryonic OSNs (199).

Many studies offered supportive evidence for expression of TRPM5 in MVCs using Trpm5-GFP mice. For instance, morphological and immunocytochemical properties of the TRPM5-expressing MVCs in the MOE were described, as well as evidence for voltage-gated Na⁺ currents and Ca²⁺-activated cation currents using patch-clamp recordings (196). Using two-color in situ hybridization method, it was found that transcription factor Skn-1a co-expressed with TRPM5 in MOE of embryonic and adult mice, and deficiency of Skn-1a abolished the expression of TRPM5 in MOE (200). It was concluded that Skn-1a/Pou2f3 is indispensable for generation of TRPM5-expressing MVCs in the murine MOE. TRPM5-exressing MVCs share similar components of transduction signaling cascade with solitary chemosensory cells (SCCs) but, unlike SCCs, they possess only sparse trigeminal innervation (201). Two additional studies also showed the expression of TRPM5 in the olfactory epithelium (202, 203).

Interestingly, TRPM5-mediated chemosensation also exists in intestinal tissues and the pulmonary system. Duodenal enteroendocrine cells appear to use it to regulate endogenous opioids release (204). This sensory function of TRPM5 was found to influence insulin release, which will be discussed in the next section. TRPM5 in tracheal brush cells is important for acetylcholine release in response to bitter substances released by bacteria (205). TRPM4 has been found to also contribute to taste sensation in peripheral taste receptor cells, where PLCβ3 instead of PLCβ2 mediates taste signal transduction (206, 207).

Many studies revealed abundant TRPM5 expression in the primates or rodents GI tract from esophagus to large intestine. A broad expression profile of TRPM5 mRNA in human GI tract biopsy samples with or without type II diabetes was observed (208). High-level TRPM5 mRNA expression was also detected in human and monkey stomach and intestine tissue (78, 184). Interestingly, TRPM5 mRNA and protein have been shown to be upregulated in morbidly obese patients compared to normal weight people (209). However, a similar inverse correlations with blood sugar concentration in both normal and diabetic groups was also reported (208). In rodents, many studies detected TRPM5 mRNA or protein expression in GI tract, mostly in the intestine and a few in the stomach (172, 178, 187, 202, 204, 208, 210–214). A systematic TRPM5 immunoreactive profiling in rodent detected solitary TRPM5-positive cells with brush cell markers throughout the GI tract and respiratory system (202). Another study also described that TRPM5-expressing intestinal cells are mostly brush cells (210). To explore the biological role of TRPM5 in these tuft cells, one study noticed that SCCs co-expressing TRPM5 and endogenous opioids exist in duodenum, suggesting that TRPM5 is required for secretion of these opioid peptides (204). It has also been suggested, based on evidence from Trpm5-eGFP mice and Trpm5-null mice, that TRPM5-expressing tuft cell could mediate tuft cell response to intestinal parasites (212).

TRPM5 channels are found to be critical for small intestinal remodeling in responding to helminths and protists, which requires TRPM5-expressing type 2 innate lymphoid cells (ILC2) (215, 216). It also regulates mucin secretion from colon goblet cells (217) in cooperation with the sodium/calcium exchanger NCX (218). Knocking out Trpm5 abrogates accumulation of the taste-chemosensory tuft cells in intestine, the primary source of the parasite-induced cytokine interleukin-25 (212). In B lymphocytes, TRPM5 channels were found to regulate calcium responses to influence proliferation and inflammatory responses (219). TRPM5 channels are also suggested to contribute to thymic function (220).

In addition to the GI tract section, Kaske et al. described a detailed distribution pattern of TRPM5 protein in the rodent respiratory system using immunohistochemistry (IHC). They found TRPM5-expressing tuft cells in nose, trachea and bronchus (202). TRPM5 mRNA in murine trachea and lung was also detected and found to be upregulated in diet-induced obesity mice only in trachea compared to control group (159). In addition, based on observations from Trpm5-GFP mice, IHC, and event-related potential (ERP) recording as well as calcium imaging, TRPM5-expressing SCCs in murine nasal cavity are suggested to respond to odorous irritants and play an essential role in monitoring inhaled air quality (221). A comparative study of TRPM5 expression in human nasal tissues from patients with or without rhinitis found that both groups showed similar TRPM5 mRNA expression levels (222).

f. TRPM4 and TRPM5 in pancreas endocrine release

Insulin release by beta-cells is accompanied by both an increase in intracellular calcium concentration and membrane depolarization. It is well-established that L-type voltage-gated Cav channels and K_ATP channels participate in these signaling events (128), though CAN channels have been recorded in pancreatic acini as early as the 1980s (223). Now it is well-established that TRPM4 and TRPM5 are expressed in pancreas beta-cells and alpha-cells. Since their activities can contribute to both calcium signaling and electrical signaling, it is attractive to hypothesize that these channels play a role in regulating insulin release (Figure 12). Indeed, it was observed that suppressing TRPM4 expression led to significantly decreased insulin secretion from rat pancreatic beta-cell line INS-1 cells upon glucose or arginine vasopressin stimulus (224). Increases in TRPM4 activity can be the result of intracellular calcium release (representing a rapid phase upon calcium application) and triggered TRPM4 trafficking and insertion into plasma membrane (representing a second phase that took minutes) (224). In pancreatic acinar cells, evidence suggests that TRPM4 serves as a linkage between calcium signaling and membrane potential (225). It has been shown that the natural plant products steviol glycosides enhance pancreatic beta-cell function (and taste sensation) by potentiation of TRPM5 activity (226).

Figure 12. — Physiological function of TRPM4 and TRPM5 in pancreas beta-cells at low (A) and high (B) blood glucose levels. Solid red arrows indicate calcium flow; dash arrows indicate calcium regulation targets. Solid black, deep blue arrows indicate sodium and potassium flow, respectively. Endoplasmic reticulum serves as an important intracellular calcium store for beta-cells but is omitted due to space limitation. Only selected ion channels are shown. GLUT-2, glucose transporter 2; G-6-P, glucose 6-phosphate.

Additional evidence supports a role TRPM4 plays in insulin secretion. TRPM4 mRNA was identified in the pancreas (13). The presence of TRPM4 at mRNA and protein levels in both alpha-cells (227, 228) and beta-cells (224, 228) has been reported. Currents with TRPM4 characteristics were recorded from the mouse pancreatic alpha-cell line αTC1–6 (227). The increase in PIP2 level in beta-cells upon glucose-induced activation may potentiate TRPM4 activity. In addition, the glibenclamide is known to inhibit TRPM4 (56). Indeed, application of 9-phenanthrol inhibited insulin secretion from rat islets of Langerhans (229). Glucagon-like peptide 1 (GLP-1) is an incretin hormone working through the cAMP/PKA (protein kinase A) and PLC/PKC signaling pathways (230). It was observed that, when applied to mouse islets, GLP-1 caused membrane depolarization, increased action potential firing, and enhanced insulin secretion even in the presence of K_ATP channel blocker tolbutamide and the L-type calcium channel blocker isradipine; the effects could be reduced by lowering extracellular concentration of TRPM4-permeating Na⁺ ions (231). The GLP-1 effects are thought to be due to the PKC and ATP sensitivity of TRPM4. In the αTC1–6 cell line, suppressing TRPM4 expression reduced intracellular calcium signaling and glucagon secretion (227).

Like TRPM4, TRPM5 may also participate in regulating insulin secretion. It was found that knocking out TRPM5 suppresses glucose-induced calcium oscillation in pancreatic islets which may lead to glucose tolerance (232); insulin in turn downregulates pancreatic islet TRPM5 expression (233). Several studies reported the detection of endogenous TRPM5 expression in rodent beta-cell lines as well as human pancreatic islets. In support of TRPM5 mRNA expression in beta-cells from various species, whole-cell patch-clamp recordings of rat beta-cells revealed a transient current activated by intracellular calcium that exhibited outward rectification and calcium concentration dependence similar to those seen in TRPM5-expressing HEK293 cells (17). Expression of TRPM5 in pancreatic beta-cells at mRNA and protein level was also detected using qPCR and immunostaining techniques; a calcium-activated cation current in single pancreatic islet cells was likely mediated by TRPM5 based on the differences in current pattern in Trpm5 KO and wild-type mice (232). The detected level of TRPM5 mRNA reduced in isolated pancreatic islets from diabetic-obese (db/db) and ob/ob mice, and insulin downregulated TRPM5 mRNA expression in pancreatic islets from leptin-deficient type II diabetes murine models (233). In summary, these findings indicate that, in addition to TRPM4, TRPM5 in beta cells is important in regulating insulin release and glucose levels in mammals.

As mentioned earlier, the chemo-sensing function of TRPM5 in intestine allows it to participate in regulating pancreas function and insulin release, and its malfunction may contribute to metabolic diseases. In a rat Type II diabetes model, high expression of TRPM5 mRNA in ileum rather than duodenum was observed and, interestingly, TRPM5 expression was downregulated in ileum of diabetic rat (211). However, quinoa was found to reduce upregulated TRPM5 protein in colon from a mouse type II diabetes model in another study (214). This discrepancy might be due to the difference of species and sampled tissues. In addition, a study of obesity observed considerable enrichment of TRPM5 mRNA in murine duodenum, which was downregulated in diet-induced obese mice group (159). Interestingly, one group observed that monosodium glutamate (MSG) could increase cholecystokinin (CCK), a hormone known for reducing food intake, accompanied by elevated expressions of taste receptor and TRPM5 mRNA in rat duodenum (213). Consistent with findings of TRPM5 functions in taste cells, it is reported that the sweet taste receptor in beta cells also relies on PLC and TRPM5 for signaling (234).

g. Additional potential functions

TRPM4 expression was detected in the human and rodent urogenital system including bladder, uterus, kidney, prostate, testis, and placenta. Using rodent bladder tissues, Yu et al. conducted a systematic study of TRP channel expression at the mRNA and protein levels, and identified that TRPM4 has a relatively high expression level in urothelium (235). Consistent with the evidence of TRPM4 mRNA and protein expression in rat detrusor smooth muscle (DSM) by means of RT-PCR, WB and immunostaining, patch-clamp recordings demonstrated that 9-phenanthrol could significantly reduce the spontaneous inward current activity in freshly isolated rat DSM cells (236). Similar results were obtained with guinea pig or human DSM and support that TRPM4 plays a critical role in human and rodent DSM excitability and contractility (237, 238). Indeed, age-dependent decrease in TRPM4 expression could attenuate urinary bladder smooth muscle contractility (239). Additional functional evidence supports a potential role of TRPM4 in detrusor overactivity after spinal cord transection in mice (240). Potential linage between TRPM4/TRPM5 channels and cancer has been discussed in a recent review (241).

Both TRPM4 and TRPM5 may help control breath patten (161, 166, 242). TRPM5 in particular mediates tracheal brush cell activation (243). In mice, TRPM4 contributes to uterine contraction (244). Multiple lines of evidence from RT-PCR, WB, electrophysiology, calcium imaging, as well as TRPM4 shRNA indicate that TRPM4 in human adipose-derived stem cells (HASCs) mediates histamine-induced calcium signaling (245). TRPM4 expression in uterus was revealed by mRNA expression in human and murine endometrium, suggesting a role in endometrium function (78, 246–248).

Although TRPM4 expression in kidney (13, 78, 79, 85, 158, 249), prostate (78, 237, 250), testis (79, 251), and placenta (13, 78) has been reported, the functional role of TRPM4 in these organs is still unknown. In addition, TRPM4 mRNA or protein was detected in human and rodent lung (78, 79, 85), liver (13, 78, 85), stomach and intestine (78), tongue (158), skeletal muscle (13, 158, 252), inner ear (253, 254), breast (255), and adipose (78, 245). TRPM5 expression in human and rodent heart (158), prostate (78), skin (256), odontoblast (257), and kidney (78, 158, 161, 187, 189) was also detected. Function of TRPM4 and TRPM5 in these tissues or cells remains to be examined.

9. Human diseases and transgenic animal models

When various splice variants of TRPM4 were cloned and examined functionally (12, 13), their resemblance to the CAN channels was immediately recognized. However, CAN currents had been recorded from many cell types. What might be the physiological role of the cloned TRPM4 channels in these cells? An exciting early finding came from a gene linkage study of progressive familial heart block type I (PFHBI) patients (96). PFHBI is an autosomal-dominantly inherited heart disease of the His-Purkinje system that progressively disrupts cardiac electrical conduction. The study of one large pedigree revealed an E7K mutation in TRPM4 (96). Located at the N-terminal end of the channel, this mutation does not appear to affect TRPM4’s function; nonetheless, the mutant channels were found to accumulate abnormally at the cell surface. This was caused by attenuation of deSUMOylation of the TRPM4 protein that impaired endocytosis. Subsequently, gain-of-function TRPM4 mutations due to disrupted endocytosis and resultant elevated surface expression have been described in numerous reports of patients suffering from the Brugada syndrome and the long QT syndrome (Figure 13, left). This mounting evidence, together with earlier reports of CAN channels in the cardiovascular system, strongly suggests a role of TRPM4 in regulating normal cardiac electrical conduction. However, even if the heart diseases are caused by a gain of TRPM4 function, logically it remains possible that TRPM4 current does not contribute significantly to the electrical activity of a normal heart. It is further noticed that another calcium-activated cation channel, SK2, exists in the heart; being a potassium-selective channel, the functional role of SK2 would be to convert a calcium signal into membrane hyperpolarization (91). Interestingly, reports of cardiac diseases linked to loss-of-function TRPM4 mutations start to emerge (Figure 13, right).

Figure 13. — Location of human TRPM4 mutations linked to cardiac and skin diseases, shown on two subunits. (A) The gain-of-function (GOF) mutations associated with skin (magenta) and cardiac diseases (orange). (B) The loss-of-function (LOF) mutations associated with cardiac diseases (red).

In addition to naturally occurring channel mutations, it is found that the transcription factor p53 can also affect the expression level of TRPM4 (258). The process may play a role in cancer cells in which expression of TRPM4 has been found to be upregulated; it is suggested that overexpression of TRPM4 may contribute to increased adhesion, migration, proliferation, and invasion (255, 259–265). Increased TRPM4 activity can also be achieved by activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), resulting in arrhythmogenicity (266). Protein tyrosine phosphatase non-receptor type 6 (PTPN6) can affect the surface level of TRPM4 through direct binding (267).

The identification of two TRPM4 gain-of-function mutants in PSEK patients called for attention of the channel’s potential physiological role in the skin (136) (Figure 14A). PSEK is a severe skin disorder characterized by early-onset, slowly progressive, symmetrical, erythematous skin plaques predominantly on the extensor aspect of the extremities (Figure 14B&C). Both identified mutations are in the S6 segment that lines the ion permeation pore (Figure 13, left). They are both gain of function in nature, yielding higher calcium sensitivity in the mutant channels (Figure 14D&E); increased channel activity leads to elevation of the resting membrane potential. Surface expression level was pointedly checked but no change was detected. Enhanced cell proliferation was observed in patient skin tissue and mutant channel-expressing cell-line cells. Interesting, while the severe skin phenotype started shortly after birth and progressed during development, this progression stopped at puberty and gradually reversed itself. It is yet unknown what developmental change underlines this peculiar course. Even more intriguingly, none of the 21 PSEK patients was found to exhibit any detectable heart defect, and a skin problem has not been mentioned for the heart disease patients associated with TRPM4 gain-of-function mutations affecting trafficking (summarized earlier) or gating (268).

Figure 14. — TRPM4 gain-of-function mutations cause progress symmetric erythrokeratodermia (PSEK). A. Two example pedigrees containing the I1040T mutation. B. Erythematous hyperkeratotic plaques on the patient’s hands and feet. C. Affected skin shows psoriasiform hyperplasia with focal parakeratosis and mild perivascular lymphocytic infiltration in the superficial dermis. D. Increased current responses of TRPM4 mutants. E. Comparison of the I-V relationship between TRPM4 wildtype and mutants. Modified from Wang et al. (136) with permission.

There is so far no report of human immune system disease that is directly linked to genetic defects in TRPM4. Nonetheless, changes in the level of TRPM4 expression have been observed in patients. A survey among TRP channels of peripheral blood mononuclear cells of inflammatory bowel disease patients suggested that TRPM4 expression might be negatively correlated with severeness of ulcerative colitis (135). Evidence for TRPM4 over-expression in acute myeloid leukemia patients was reported, and small interfering RNA inhibition of TRPM4 expression led to cell cycle arrest in lysine [K]-specific methyltransferase 2A (KMT2A)-rearranged leukemia cells (269). However, a survey of 64 multiple sclerosis patients found no change in the TRPM4 mRNA level compared to healthy controls (134). This finding was later confirmed in a survey of 30 relapsing-remitting multiple sclerosis patients (133). This group nonetheless observed a decrease in TRPM4 mRNA level in psoriasis patients (130). Again, it is unknown why no abnormality in heart health was found in these patients, just like no immune system disease was observed in heart or skin diseases patients carrying a TRPM4 gain-of-function or loss-of-function mutation.

Many studies examined mouse models with disruption of the Trpm4 gene; some have been mentioned earlier. In support of a role TRPM4 plays in the cardiovascular system, cardiac muscle of Trpm4^−/− mice exhibited abnormalities in ß-adrenergic inotropic response and duration of cardiac action potential (270). The Trpm4^−/− mice exhibit cardiac hypertrophy and multilevel conduction blocks (88). TRPM4 also contributes to smooth muscle functions (113). Bone marrow-derived mast cells from TRPM4 knock-out mice exhibited increased calcium entry and degranulation upon stimulation, released more histamine, leukotrienes and tumor necrosis factor (132). These Trpm4^−/− mice exhibited exaggerated IgE-mediated acute passive cutaneous anaphylactic response. In another study, dendritic cells from Trpm4^−/− mice exhibited impaired chemokine-induced migration, with a concomitant downregulation of the expression of phospholipase C that is thought to be due to calcium overload (131). Interestingly, maturation of dendritic cells was not hindered by the elimination of TRPM4 current, only migration was affected. This might be expected if the role of TRPM4 activity is to limit calcium entry through plasma membrane. In supporting this idea, migration of bone marrow-derived mast cells was found to be hindered by knocking out Trpm4, which appeared to be due to reduction in F-actin formation (271). It is found that, in migrating T cells, TRPM4 channels relocalize to the leading-edge (272). Suppression of TRPM4 function due to methyltransferase-induced production of non-functional TRPM4 splicing variant proteins leads to reduction in interleukin-2 production in mouse T cell (273). In addition, TRPM4 deletion increased mouse mortality in a model of sepsis (274). It is important to note that the gene knock-out approach (and knock-in approach discussed below) has a global effect on all tissues and cells that express the channel. Observations obtained from these mice need to be confirmed with experimental methods with better specificity.

The only TRPM4 gain-of-function mouse model reported so far carries the human I1033M mutation that increases the channel’s calcium sensitivity and is linked to a severe form of skin disease, as mentioned earlier (136, 139). The mice exhibited no abnormality in the skin under specific pathogen-free conditions; they bred well and showed no noticeable health issue. However, upon imiquimod challenges, they presented more severe psoriasiform dermatitis than wildtype mice (139). Greater accumulation of CCR6-expressing γδ T cells and higher mRNA levels of Il17a were observed; dendritic cells showed enhanced migration. Increased keratinocyte proliferation was also observed.

No human disease has been linked to changes in genetic coding or expression level of TRPM5. Nonetheless, knocking out of Trpm5 in mice revealed the channel’s physiological role as the effector of taste transduction (45). Just like knocking out PLCβ2, a key mediator of the taste transduction pathway, knocking out Trpm5 abolished sweet, bitter and umami taste reception (while leaving sour and salty tastes unaffected). This landmark study highlighted the functional role of TRPM5 in taste perception and, despite a report of detectable umami reception in another TRPM5 knock-out mouse model (173), attracted intensive studies of the role of TRPM5 in chemosensory physiology. Knocking out TRPM5 reduced bitter aversion (275) and metallic taste (276). It was quickly found that TRPM5 expressed in olfactory neurons participates in sensing semiochemicals (such as pheromones) (190). It was found that the TRPM5-expressing olfactory sensory neurons (OSNs) mediate pheromone transduction via a novel pathway that distinct from a canonical CNG channel-ANO2 channel coupling pathway (197). In another study, based on previous electroolfactogram (EOG) observations that Trpm5 knock-out mice showed similar responses to pheromones (and odors) compared to wild-type mice, EOG recordings were conducted with Trpm5 KO mice under unilateral naris occlusion condition. It was observed that Trpm5-null mice were less sensitive to putative pheromones than wild-type mice, and the number of OSNs expressing TRPM5 increased in wild-type mice with naris occlusion (198).

In addition to the roles in sweet, umami and bitter perception, TRPM5 was found to also mediate fat taste perception (180, 189). In support of this view, the long-chain unsaturated free fatty acid linoleic acid (LA) activates TRPM5 channels expressed in murine taste buds, thereby depolarizing taste cells and inducing a robust intracellular calcium rise. In single taste cells isolated from Trpm5-null mice tongue, LA-induced inward current and intracellular calcium rises were substantially decreased; consistent with the results from in vitro study, Trpm5-null mice could not distinguish LA compared to wild-type and were less sensitive to LA, indicating that TRPM5 plays an essential role in the LA-transduction pathway.

Even though TRPM4 has been proposed to regulate insulin release, no hyperglycemia, insulin deficiency, or diabetes mellitus was reported for the Trpm4 knock-out mice. Nonetheless, effects of the incretin hormone glucagon-like peptide 1 (GLP-1) could not be observed in Trpm4 or Trpm5 knock-out mice islets (231). Trpm5 knock-out mice however exhibited noticeable glucose intolerance—the blood glucose level was seen elevated for more than an hour compared to the wildtype, and hyperglycemia and arginine-induced insulin secretion was diminished in pancreatic islets (277).

10. Conclusion

The unique combination of being monovalent cation-selective in permeation and calcium sensitive in activation bestow TRPM4 and TRPM5 unique powers to influence cellular physiology. While their contributions as the unidentified CAN channels had been well documented, molecular cloning at the turn of century and recent high-resolution structural revelation set the stage for detailed investigation of their physiological functions. Their critical roles in a number of cellular signaling processes start to emerge. Despite these exciting developments, the biophysical properties of TRPM4 and TRPM5 are not fully characterized. Their calcium sensitivity under physiological conditions and factors influencing the sensitivity remain to be elucidated. Pharmacological tools with high selectivity are still lacking. These limitations add to the challenge in deciphering their physiological roles. The recent comparative study of TRPM4 structures at near body core temperatures and at the room temperature or lower (26) highlights the need to investigate heat-sensitive TRPM4 and TRPM5 channels (63) at conditions more closely resembling real physiology. Nonetheless, the intensive investigation being attracted to these channels will likely yield a much better understanding of the physiology, pharmacology, and pathology related to TRPM4 and TRPM5 in the near future, which will open the possibilities to address pathophysiological conditions related to their dysregulation or genetic variations.

Clinical Highlights.

Calcium and membrane potential are two prominent cellular signals. They are involved in virtually every aspect of physiology and are implicated in numerous pathological conditions. TRPM4 and TRPM5 ion channels offer a direct linkage between these two signals.
TRPM4 and TRPM5 are found to contribute to fundamental physiological processes such as cardiovascular function, immune response, pancreas endocrine release, taste reception, and others.
Many hereditary gain-of-function or loss-of-function TRPM4 mutations have been linked to cardiovascular diseases such as Brugada syndrome, long-QT syndrome, conduction block, and a severe skin disease progress symmetric erythrokeratodermia (PSEK). Knocking out Trpm5 in mice abolished sweet, bitter and umami taste reception.

Acknowledgements

We thank Don Bers, Mike Cahalan, Byung Chang Suh, and many other colleagues for insightful discussions. We regret the space limitation prevents citation and discussion of most of the over 1000 original reports and review articles in this active research field. Research on TRPM4 and TRPM5 in the Zheng lab is funded by NIH grant R01NS128180.

Footnotes

Activities of many other TRP channels are also sensitive to calcium, hence may contribute to chemical-to-electrical signal conversion. While noticeable similarities have been noticed—for example, the calcium-binding site in the transmembrane domain shared by multiple TRPM and TRPC channels—this review focuses on TRPM4 and TRPM5 and mentions other ion channels only when directly relevant.

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PERMALINK

The TRP Channels Serving as Chemical-to-Electrical Signal Converter

Yuhua Tian

Jie Zheng

Abstract

1. Introduction

2. The CAN channels and their molecular cloning

Figure 1.

3. Structural features of TRPM4 and TRPM5

Figure 2.

Figure 3.

4. Activation and desensitization

Figure 4.

5. Channel regulation mechanisms

a. Membrane potential

b. Calmodulin

c. PIP2

d. ATP, PKC and polyamine

e. Temperature

6. TRPM4 and TRPM5 pharmacology

Table 1.

7. Tissue and organ distribution

Table 2.

Figure 5.

Table 3.

Figure 6.

8. Potential functional roles in physiology

Figure 7.

a. TRPM4 in the cardiovascular system

Figure 8.

Figure 9.

b. TRPM4 in the immune system

Figure 10.

c. TRPM4 in Skin Health

d. TRPM4 and TRPM5 in the Nervous system

e. TRPM5 in the sensory system

Figure 11.

f. TRPM4 and TRPM5 in pancreas endocrine release

Figure 12.

g. Additional potential functions

9. Human diseases and transgenic animal models

Figure 13.

Figure 14.

10. Conclusion

Clinical Highlights.

Acknowledgements

Footnotes

Reference

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