TRPM4 channels
References

Characterization of a mutant fruit discovered that was defective in light sensing and exhibited only "transient light-induced receptor potentials" (TRPs) instead of the normal maintained response led to the identification of TRP channels (Cosens and Manning, 1969). The large human TRP gene family encodes  transient receptor potential (TRP) proteins that form nonselective cation channels largely located in the cell membrane, modulating ion entry, although they are also expressed in various organelles of most cell types and tissues.
In mammals, 28 TRP channel genes have been identified that can be divided into six sub-families (Owsianik et al., 2006; Nilius and Szallasi, 2014):

• TRPC (canonical): TRPC1, TRPC2, TRPC3/TRPC6/TRPC7, and TRPC4/TRPC5.TRPV (Vanilloid): TRPV1/TRPV2, TRPV3, TRPV4, and TRPV5/TRPV6.
• TRPM (melastatin): TRPM1/TRPM3, TRPM4/TRPM5, and TRPM6/TRPM7 with TRPM2 and TRPM8.
• TRPA (ankyrin): TRPA1
• TRPML (mucolipin): TRPML1-3.
• TRPPP (polycystin): TRPP1 (PKD2), TRPP2 (PKD2L1) and TRPP3 (PKD2L2).

TRP channels exhibit diverse permeation and gating properties, can be activated by a wide variety of stimuli including many post-transcriptional mechanisms (i.e. phosphorylation, G-protein receptor coupling, ligand-gating, and ubiquitination), physical (voltage, temperature, force, pressure, and tension) and chemical (both endogenous and exogenous) stimuli and because they are widely expressed, they are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways (Nilius and Szallasi, 2014). Most TRP channels are regulated by phosphoinostides, such as PtIns(4,5)P2 and IP3 although the effects reported are often complex, an occasionally contradictory (Nilius and Szallasi, 2014).
They act very important regulators of intracellular Ca²⁺ signaling in diverse cell types, either by providing a Ca²⁺ influx pathway, functioning as intracellular calcium release channels or by depolarising the membrane potential, which on one hand triggers the activation of voltage-gated Ca²⁺ channels, and on the other limits the driving force for Ca²⁺ entry (Alonso-Carbajo et al., 2017).

Several members of the TRP family (TRPC1, TRPC3-7, TRPV1, TRPV2, TRPV4,TRPM2, TRPM4, TRPM6, TRPM7, TRPP2. Subtypes are expressed in cardiomyocytes, fibroblasts, endothelial cells and vascular smooth muscle cells (Alonso-Carbajo et al., 2017). However, we shall focus our attention in the TRPM4 channel.

TRPM4 channels na

TRPM4 gene is located on human chromosome 19 and encodes a 1214-amino-acid protein. The Transient Receptor Potential Melastatin 4 (TRPM4) channels present six transmembrane spanning regions (S1-S6), a pore-forming loop between S5-S6 and their C termini and N termini are intracellular. The functional channel is a homotetramer. TRPM4 has calmodulin-binding sites, Walker B motifs, ATP, and phosphatidyl inositol 4,5-bisphosphate (PIP2) binding sites, a glycosylation site and putative phosphorylation sites for protein kinase A (PKA) and protein kinase C (PKC) (Guinamard et al., 2015).

TRPM4 channels are highly expressed in sino-atrial node cells, in atrial cells, in the Purkinje system and the right ventricle (Launay et al., 2002; Liu et al., 2010; Mathar et al., 2014; Kruse and Pongs, 2014). They present a single-channel conductance close to 25 pS (within the range of 60 to +60 mV), are permeable to monovalent cations, but impermeable to Ca²⁺, present strong outward rectification, slow activation at positive potentials and rapid deactivation at negative potentials (IUPHAR).
Because of their high na+ permeability and significant inward currents at physiological resting potentials, TRPM4 channnels can modulate membrane depolarization and therefore regulate cellular function (Owsianik et al., 2006). TRPM4 channels are a molecular candidate for the Ca²⁺-activated non-selective non-selective monovalent cationic current (NSCCa) described in cardiomyocytes from adult mice, rats, and humans (Mattar et al., 2014).
TRPM4 channels can play a role in the spontaneous diastolic depolarisation and regulation of sinus automaticity in sino-atrial myocytes (Hof et al., 2013) and contribute to regulate atrial repolarization (Demion et al., 2014; Hof et al., 2013; Simard et al., 2013). Indeed, isolated atria from Trpm4−/− mice exhibited an AP that was 20% shorter compared to WT action potentials which confirm that TRPM4 channels are implicated in the waveform of the atrial action potential (Simard et al., 2013). At negative membrane potentials TRPM4 channels catalyze na⁺ entry into the cell, leading to cellular membrane depolarization; at positive membrane potentials, TRPM4 channels may catalyze cellular K⁺ efflux, leading to membrane repolarization.

In Trpm4-/- mice, cardiac muscle displays an increased β-adrenergic inotropic response and APD show a decreased time for 50% and 90% repolarization which leads to an increased driving force for the L-type Ca²⁺ current during the action potential, increased Ca²⁺ transients and a stronger inotropic effect after b-adrenergic stimulation. These results suggest that TRPM4 is a novel modulator of the b-adrenergic response in the ventricular myocardium of the mice.

Dominantly inherited mutations in the TRPM4 gene have been identified in patients with progressive familial heart block type I (PFHBI) and isolated cardiac conduction disease (ICCD) giving rise to atrio-ventricular conduction block (AVB), right bundle branch block, bradycardia, and the BrS (Kruse and Pongs, 2014).

References

Alonso-Carbajo L; Kecskes M, Jacobs G, et al. Muscling in on TRP channels in vascular smooth muscle cells and cardiomyocytes. Cell Calcium 2017;66:48-61.

Cosens DJ, Manning A. Abnormal electroretinogram from a Drosophila mutant. nature 1969;224:285–287.

Guinamard R, Bouvagnet P, Hof T, et al. TRPM4 in cardiac electrical activity. Cardiovasc Res. 2015;108:21-30.

Hof T, Simard C, Rouet R, et al. Implication of the TRPM4 nonselective cation channel in mammalian sinus rhythm. Heart Rhythm 2013;10:1683–1689.

International Union of Basic and Clinical Pharmacology TRP Channel Database (www.iuphar-db.org/index.jsp)

Kruse M, Pongs O. TRPM4 channels in the cardiovascular system, Curr.Opin. Pharmacol. 2014;15: 68–73.

Launay P, Fleig A, Perraud AL, et al. TRPM4 is a Ca²⁺-activated nonselective cation channel mediating cell membrane depolarization. Cell 2002, 109:397-407

Liu H, Chatel S, Simard C, et al.: Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel. PLoS ONE 2013, 8:e54131.

Mathar I, Kecskes M, Van der Mieren G, et al. Increased beta-adrenergic inotropy in ventricular myocardium fromTrpm4-/- mice, Circ. Res. 2014;114:283–294.

Nilius B, Szallasi A. Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev 2014;66:676-814.

Owsianik G, Talavera K, Voets T, Nilius B. Permeation and selectivity of TRP channels.  Annu Rev Physiol 2006; 68: 685-717. Simard C, Hof T, Keddache Z, et al. The TRPM4 non-selective cation channel contributes to the mammalian atrial actionpotential, J. Mol. Cell Cardiol. 2013;59:11–19.

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