TRPM4 in Cardiac Electrical Activity

Cardiovascular Research (2015) 108,21–30 REVIEW doi:10.1093/cvr/cvv213 TRPM4 in cardiac electrical activity Romain Guinamard1*, Patrice Bouvagnet2, Thomas Hof1, Hui Liu3, Christophe Simard1, and Laurent Salle´ 1 1Groupe Signalisation, Electrophysiologie et Imagerie des Le´sions d’Ische´mie–Reperfusion Myocardique, EA4650, Universite´ de Caen Basse—Normandie, Sciences D, Esplanade de la Paix, CS 2 3 14032, 14032 Caen Cedex 5, France; EA 4173, Universite´ Lyon 1 and Hoˆpital du Nord-Ouest, Lyon, France; and Department of Anatomy, Hainan Medical College, Haikou, Hainan 571101, China Downloaded from https://academic.oup.com/cardiovascres/article/108/1/21/266658 by guest on 30 September 2021 Received 16 December 2014; revised 13 July 2015; accepted 31 July 2015; online publish-ahead-of-print 13 August 2015 + Abstract TRPM4 forms a non-selective cation channel activated by internal Ca2 . Its functional expression was demonstrated in cardiomyocytes of several mammalian species including humans, but the channel is also present in many other tissues. The recent characterization of the TRPM4 inhibitor 9-phenanthrol, and the availability of transgenic mice have helped to clarify the role of TRPM4 in cardiac electrical activity, including diastolic depolarization from the sino-atrial node cells in mouse, rat, and rabbit, as well as action potential duration in mouse cardiomyocytes. In rat and mouse, pharmacological inhibition of TRPM4 prevents cardiac ischaemia–reperfusion injuries and decreases the occurrence of arrhythmias. Several studies have identified TRPM4 mutations in patients with inherited cardiac diseases including conduction blocks and Brugada syndrome. This review identifies TRPM4 as a significant actor in cardiac electrophysiology. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords TRPM4 † Calcium-activated non-selective cation channel † Cardioprotection † Brugada † Arrhythmias 1. Introduction 2. TRPM4 expression in the heart, 2+ ACa -activated non-selective monovalent cationic current (NSCCa), with biophysics, and regulatory + no permeability for Ca2 and a single-channel conductance close to 25 pS, properties was described in the early 2000s in cardiomyocytes from adult mice, rats, 1–3 4–6 and humans. Identifying this additional cardiac NSCCa sparked new 2.1 TRPM4 expression profile in the heart investigations, which were further boosted by the concomitant cloning TRPM4 mRNA is present in a large variety of tissues from human, of the transient receptor potential melastatin 4 (TRPM4) gene in these mouse, and rat, the heart being among the major TRPM4 expressing tis- species.7–9 This gene encodes an ion channel protein (TRPM4) whose cur- sues.7,8,25,26 Several studies evaluated TRPM4 mRNA or protein ex- rent properties resemble the aforementioned NSC current and is thus Ca pression in specific parts of the heart, as collected in Table 1. TRPM4 considered as its molecular counterpart. mRNA and/or protein is expressed in nodal and conductive tissue as Three recent developments further highlighted the multiple roles of shown in the mouse sino-atrial node (SAN) and bovine bundle TRPM4 current in the heart: first, the identification of the TRPM4 in- branch.14,30 It is also detected in the atrium, including in humans,2,27 hibitor 9-phenanthrol, which helped unmask the effects of TRPM4 cur- and in the ventricle.14,21,29 Interestingly, several studies reported a sig- rent modulation on small mammals heart functions10; secondly, the nificant weaker expression in ventricles than in atria in rat, mouse, and generation of Trpm4 null mice to study the impact of gene disrup- bovine.14,19,28,31 At the functional level, TRPM4 current has been re- tion11,12; and thirdly, the discovery by positional cloning that TRPM4 corded in rodent as well as in human cardiomyocytes.2,3,19,28,31,33 In mutations are associated with cardiac conduction block and Brugada addition to cardiomyocytes, Trpm4 mRNA has also been detected in syndrome in humans.13 – 15 These contemporary studies provide a por- rat ventricular fibroblasts and arterial smooth muscle cells and human trait of the role(s) of TRPM4 both in cardiac physiology and in patho- atrial fibroblasts.23,34,35 As discussed subsequently, cardiac TRPM4 ex- physiology, as reviewed previously.16– 18 In addition to influencing pression profile can be modified by human TRPM4 gene mutations13 – cardiac development and remodelling19,20 or regulating cardiac con- 15,36 or cardiac diseases such as hypertrophy in rat.28 tractility,21 TRPM4 participates in cardiac electrical activity. This review will sharply focus on this last contribution by collecting existing data. Note that in addition to its role(s) in cardiac activity, TRPM4 is im- 2.2 TRPM4 biophysical properties plicated in other physiological functions such as the immune response, The biophysical and regulatory properties of TRPM4 were described in insulin secretion, breathing activity, smooth muscle contraction, arterial the early of 2000s7,25,37 and have been reviewed extensively.16,38 The constriction, and cell death.16,22 – 24 Trpm4 gene is located on human chromosome 19 and encodes a * Corresponding author. Tel: +33 2 31 56 51 39; fax: +33 2 31 56 54 53, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected]. 22 R. Guinamard et al. Table 1 Cardiac expression of TRPM4 mRNA, protein, and current Species Heart SAN Atrium Ventricle Conductive tissue References ....................................................................................................................................................................................... Human mRNA Launay et al.7 mRNA Nilius et al.25 mRNA, current Guinamard et al.2 mRNA, protein Zhang et al.27 mRNA mRNA mRNA (higher) Kruse et al.13 Rat mRNA mRNA (lower) Guinamard et al.28 Current Guinamard et al.28 Protein Protein Piao et al.29 Current Zhainazarov3 Downloaded from https://academic.oup.com/cardiovascres/article/108/1/21/266658 by guest on 30 September 2021 Mouse mRNA Murakami et al.8 mRNA Nilius et al.25 mRNA Jang et al.26 mRNA mRNA mRNA (lower) Demion et al.19 mRNA, protein, current Demion et al.30 Demion et al.30 Protein Protein (lower) Mathar et al.31 Current Simard et al.32 Current Mathar et al.21 Bovine Protein Protein (lower) Protein Liu et al.14 Reported currents were recorded from freshly isolated cardiomyocytes. Higher and lower indicate the level of mRNA or protein expression compared with other parts of the heart. 1214-amino-acid protein,7 whose tertiary structure features six trans- myocytes, indicating that the current can activate in an intact cell with 2+ 45 membrane domains. The functional channel is a homotetramer. physiological [Ca ]i. TRPM4 has calmodulin-binding sites, Walker B motifs, ATP, and phos- phatidyl inositol 4,5-bisphosphate (PIP2) binding sites, a glycosylation site and putative phosphorylation sites for protein kinase A (PKA) 3. Tools to unmask TRPM4 and protein kinase C (PKC).16,38 –40 contributions to cardiac electrical TRPM4-transfected HEK-293 cells develop an ionic current with a activity linear unitary current–voltage relationship and a conductance between 20 and 25 pS,7,34 similar to endogenous TRPM4 currents recorded 3.1 Pharmacological inhibitors in cardiomyocytes (Figure 1). The channel is equally permeable to 46 + + 2+ Flufenamic acid inhibits TRPM4 (IC50 ¼ 3 mmol/L), but this promis- Na and K ,butnotpermeabletoCa (permeability sequence: 47 + + + + + cuous drug also affects a variety of other channels. In addition, Na K . Cs . Li »Ca2 ).7,41 Channel open probability TRPM4 is inhibited by glibenclamide (10 mmol/L),30 spermine increases with membrane depolarization, resulting in an outwardly rec- (IC ¼ 61 mmol/L),37 and quinine (IC from 113 to 450 mmol/L),48 tifying current at the whole-cell level.7,25 50 50 but again, these drugs also inhibit other channels.38 More recently, 9-phenanthrol was shown to inhibit TRPM4 (IC50 ¼ 2.3 Regulatory properties of the TRPM4 17 mmol/L).10 It can be applied to the inside or the outside of the mem- current brane and most probably acts directly on the channel as it is effective in 10 The intracellular effector PKC as well as PIP2 and oxygen species such cell-free patches. 9-Phenanthrol has been tested on other channels, 1,42 – 44 as H2O2 increases TRPM4 activity. Conversely, TRPM4 activity is including various transient receptor potential (i.e. TRP) channels inhibited by internal adenine nucleotides such as ATP and ADP.37 (including TRPC3, TRPC6, TRPM5, and TRPM7), and so far has shown 2+ 10,49 – 51 Ca activates the TRPM4 channel with an EC50 up to 370 mmol/L a specificity for TRPM4 within this family. Nevertheless, high when measured in the inside-out configuration, but from 20 to concentrations of 9-phenanthrol (0.1 mmol/L) inhibit the delayed out- + + 0.5 mmol/L in the whole-cell configuration after overexpression in ward rectifier K current and the voltage-gated Ca2 current in mouse cell lines.7,42 This discrepancy unmasks that TRPM4 sensitivity to cardiomyocytes, whereas lower concentrations do not.32 Further- 2+ 42,43 2 Ca is modulated by regulators such as calmodulin and PIP2. more, a recent study showed that 9-phenanthrol inhibits the Cl chan- Inside-out recordings of TRPM4 current from human atrial cardiomyo- nel TMEM16A over a concentration range that was previously 52 cytes

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