Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

Abstract

Cardiac voltage‐gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC‐related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life‐threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart‐related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well‐studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.

Inhibitory Effects of Nobiletin on Voltage-Gated Na+ Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method

“…Ion channels are essential building blocks of various action potential currents in cardiac myocytes, and voltage-gated ion channels are crucial for understanding their structures, distributions, interactions, and functions [ 6 ]. The Na + channel current ( I Na ), which begins with the activation of voltage-gated Na + channels encoded by SCN5A , is the most important part of the 0 phase of the entire action potential [ 7 ].…”