Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies

Abstract

The Transient Receptor Potential Melastatin 4 (TRPM4) is a transmembrane N-glycosylated ion channel that belongs to the large family of TRP proteins. It has an equal permeability to Na⁺ and K⁺ and is activated via an increase of the intracellular calcium concentration and membrane depolarization. Due to its wide distribution, TRPM4 dysfunction has been linked with several pathophysiological processes, including inherited cardiac arrhythmias. Many pathogenic variants of the TRPM4 gene have been identified in patients with different forms of cardiac disorders such as conduction defects, Brugada syndrome, and congenital long QT syndrome. At the cellular level, these variants induce either gain- or loss-of-function of TRPM4 channels for similar clinical phenotypes. However, the molecular mechanisms associating these functional alterations to the clinical phenotypes remain poorly understood. The main objective of this article is to review the major cardiac TRPM4 channelopathies and recent advances regarding their genetic background and the underlying molecular mechanisms.

Figure 1

Overall structure of human full-length TRPM4 in the apo state. (a, b) Side and top views of the cryo-EM reconstruction density map of human TRPM4 at 3.7 Å overall resolution. (c, d) Ribbon diagrams representing the same orientation and colors with the channel's dimensions indicated. (e) Structural details of a single human TRPM4 subunit. (f) Linear diagram depicting the major structural domains, color coded to match the ribbon diagram. The N-linked N992 glycosylation site (N-G) and the Cys993-Cys1011 disulfide bond are indicated; reprinted from [2].

Figure 2

Brugada syndrome ECGs. (a) Spontaneous type 1 ST-segment elevation. (b) Unmasking of ST-segment elevation by a pharmacological sodium channel blocker, pilsicainide. Under baseline condition, type 2 ST-segment elevation is recorded in lead V2. Pilsicainide injection (30 mg) unmasks type 1 electrocardiogram (ECG) in lead V2. (c) Unmasking of type 1 ECG by recordings of right precordial (V1–V2) leads at the third and second intercostal spaces. Adapted and reprinted with permission from [52].

Figure 3

Schematic representation of ventricular action potentials and related ECG signals. (a, b) Normal and prolonged ventricular action potential and it related QT interval. (c) Schematic representation of ECG recording presenting the onset of Torsades de Pointes in a patient with long QT syndrome. Adapted from [77].