Physiological Roles of TRPM4 in the Heart

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1		Yaopeng Hu	--	1135	2023-07-25 14:50:16

This entry is adapted from the peer-reviewed paper 10.3390/ijms241411798

The transient receptor potential melastatin 4 (TRPM4) channel is a non-selective cation channel that activates in response to increased intracellular Ca²⁺ levels but does not allow Ca²⁺ to pass through directly. It plays a crucial role in regulating diverse cellular functions associated with intracellular Ca²⁺ homeostasis/dynamics. TRPM4 is widely expressed in the heart and is involved in various physiological and pathological processes therein. Specifically, it has a significant impact on the electrical activity of cardiomyocytes by depolarizing the membrane, presumably via Na⁺ loading.

TRPM4 channel Ca2+ homeostasis cardiac electrophysiology

1. Introduction

The transient receptor potential melastatin 4 (TRPM4) channel is a Ca²⁺-activated non-selective cationic (NSca) channel, with a unitary conductance of approximately 20pS ^[1]. The TRPM4 channel protein is ubiquitously expressed in many kinds of cells, where it participates in intracellular Ca²⁺ homeostasis and modify excitability by influencing the membrane potential. Among the widespread expressed tissues, TRPM4 protein is also abundant in the heart ^[2]. Several lines of evidence suggest that TRPM4 channels may be involved in arrhythmogenicity in the heart, with both inherited and acquired traits. For example, a gain-of-function mutation (GOF) on its distal N-terminal domain has been reported to produce degenerative changes in the cardiac Purkinje system, and has been identified in a few pedigrees of Jewish and French families that manifest progressive conduction blocks and associated sudden death ^[3]. In spontaneously hypertensive rats (SHRs), long-term pressure overload produces hypertrophic changes in the heart accompanied by upregulation of TRPM4 channel proteins and their excessive activities ^[4]. These changes are further associated with the prolongation of QT interval in electrocardiogram, which is a risk factor for lethal arrhythmias. In murine hearts exposed to acute anoxic insults, early afterdepolarization (EAD)-like oscillations in the repolarization phase of action potential (AP) occur, which are selectively inhibited by a TRPM4 channel blocker, 9-phenathrol ^[5]. All these observations are consistent with the idea that the TRPM4 channel may play non-trivial roles in arrhythmogenesis.

2. Physiological Roles of TRPM4 in the Heart

(1): Contribution of TRPM4 to sinoatrial (SA) nodal and other cardiac automaticity

In the SA node (SAN), intracellular Ca²⁺ oscillations generated by the Ca²⁺ clock play a critical role in regulating cardiac automaticity. During the diastolic depolarization phase, the voltage-dependent Cav1.3 L-type Ca²⁺ channels (LTCC) activate, then Ca²⁺ influx into the SAN cell triggers Ca²⁺ release from the sarcoplasmic reticulum (SR) via the ryanodine receptors (RyR) ^[6]. A subsequent rise in [Ca²⁺]_i activates the Na⁺-Ca²⁺ exchange (NCX), which in turn extrudes Ca²⁺ from the cell in exchange for Na⁺. This generates an inward Na⁺ current that contributes to the depolarization of the membrane potential and increases the rate of pace-making diastolic depolarization (DD) ^[7].

TRPM4 channels possibly contribute to the regulation of cardiac automaticity by modulating both the Ca²⁺ clock and membrane clock in the SAN ^[8]. It has been suggested that the TRPM4 channel may contribute to the inward Na⁺ current during the DD phase ^[9]. The TRPM4 channel may also have additional effects on the cardiac automaticity, such as modulating the inward driving force for Ca²⁺ and [Ca²⁺]_i ^[10]. It has been reported that inhibition of TRPM4 channels by 9-phenanthrol reduces the heart rate in mice, rats and rabbits, suggesting that the TRPM4 channel may act as an accelerator of DD when the heart rate is decreased, to avoid bradycardia ^[9]^[11].

Overall, the TRPM4 channel plays a critical role in regulating cardiac automaticity by modulating the DD slope and [Ca²⁺]_i in the SAN, and its precise contribution to the inward Na⁺ current and the DD phase is still an ongoing focus of investigation.

(2): Role of TRPM4 channel in the atrial myocardium

The TRPM4 channel has been shown to be involved in atrial electrophysiology ^[12]. It is expressed in mice, rats, and human atrial cardiomyocytes ^[12]^[13]^[14]. The electrophysiological function of the TRPM4 channel in atrial APs was evaluated in isolated atrial cardiomyocytes by using TRPM4 knockout (Trpm4 KO) mice and a selective inhibitor, 9-phenanthrol. Inhibition of the TRPM4 channel shortened the AP duration of isolated atrial cardiomyocytes compared to those in wild-type (WT), but not knockout animals. The duration of atrial APs was also shorter in Trpm4 KO compared to WT animals ^[12].

The TRPM4 channel is reported to be responsive to shear stress induced by IP₃ receptor-mediated Ca²⁺ releases in rat atrial cardiomyocytes ^[14]. TRPM4 has also been implicated in aldosterone-induced atrial arrhythmias ^[15]. In the same study, disorganization of connexin-43 (Cx43) in atria was observed in Trpm4 KO mice, more than in WT mice. This phenomenon may be involved in the occurrence of atrial electrical disturbances. Additionally, TRPM4 channel may contribute to the growth of human and mice atrial fibroblasts; both expression and functional currents of TRPM4 has been shown to increase under cultured conditions ^[16]. Presumably, the TRPM4 channel may be engaged in some way commit to the process of atrial fibrosis ^[16]^[17].

In summary, the physiological role of TRPM4 in the atrial myocardium appears to be complex and context-dependent, with a variety of consequences observed under different conditions. It may thus be reasonable to speculate a nontrivial role(s) of TRPM4 in the pathogenesis of atrial fibrillation (AF), through alterations of both atrial electrophysiology and remodeling.

(3): Role of TRPM4 channel in the ventricular myocardium and Purkinje conduction system

The physiological role of the TRPM4 channel in the ventricular myocardium remains controversial. Discrepancies in the contribution of the TRPM4 channel between the atrium and ventricle has been reported, following comparisons of both the transcript level and functional current. Although highly detected in the atrium, the TRPM4 channel is much less expressed in the ventricular myocardium ^[18]. The definitive contribution of the TRPM4 channel to the AP duration of canine ventricular cardiomyocytes has been confirmed in the latest study by using a potent and highly selective inhibitor, 4-chloro-2-[[2-(2-chlorophenoxy) acetyl] amino] benzoic acid (CBA) ^[19]. In contrast, the Trpm4 mRNA detection and functional Ca²⁺-activated nonselective cation current were greatly enhanced in the ventricular cardiomyocytes of SHRs compared to those in the Wistar-Kyoto (WKY) rat ^[4]. The same study observed QT prolongation in SHRs, which is accompanied by an increased TRPM4 channel activity. Furthermore, the TRPM4 channel was involved in the positive inotropic effect of β-adrenergic stimulation in the ventricular myocardium ^[20].

The network of terminal Purkinje fibers (PFs) carries electrical impulses to the ventricular myocardium, playing a central role in the excitation-contraction cycle of the ventricle. PFs demonstrate a unique electrophysiology with complicated intracellular Ca²⁺ cycling ^[21]. The TRPM4 channel is most abundantly expressed in PFs, compared to the other human heart tissues ^[22], suggesting its significant contribution to the electrical properties of PFs ^[23]. The propagation failure of PFs caused by TRPM4 channel overexpression has been observed in silico ^[24]. More intriguingly, optical mapping of ectopic activation induced by mechanical stimulation in PFs demonstrated a clear link with the activation of TRPM4 channels ^[25]. The involvement of the TRPM4 channel in the electrophysiology of PFs suggests its potential role in cardiac conduction and ventricular arrhythmias.

References

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Subjects: Cardiac & Cardiovascular Systems

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Keizo Hiraishi

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Update Date: 25 Jul 2023

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1. Introduction

2. Physiological Roles of TRPM4 in the Heart

References