Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

Abstract

The voltage-gated L-type calcium channel (LTCC) is essential for multiple cellular processes. In the heart, calcium influx through LTCC plays an important role in cardiac electrical excitation. Mutations in LTCC genes, including CACNA1C, CACNA1D, CACNB2 and CACNA2D, will induce the dysfunctions of calcium channels, which result in the abnormal excitations of cardiomyocytes, and finally lead to cardiac arrhythmias. Nevertheless, the newly found mutations in LTCC and their functions are continuously being elucidated. This review summarizes recent findings on the mutations of LTCC, which are associated with long QT syndromes, Timothy syndromes, Brugada syndromes, short QT syndromes, and some other cardiac arrhythmias. Indeed, we describe the gain/loss-of-functions of these mutations in LTCC, which can give an explanation for the phenotypes of cardiac arrhythmias. Moreover, we present several challenges in the field at present, and propose some diagnostic or therapeutic approaches to these mutation-associated cardiac diseases in the future.

Dystrophin and calcium current are decreased in cardiomyocytes expressing Cre enzyme driven by αMHC but not TNT promoter

“…Secondly, the L-type calcium current density is decreased by about 40% in the MHC-Cre model. Calcium current is pivotal for cardiac excitation-contraction coupling, among other processes, and calcium current dysregulation has been implied in many cardiac arrhythmias 15 .…”

The Emerging Role of the RBM20 and PTBP1 Ribonucleoproteins in Heart Development and Cardiovascular Diseases

“…In heart cells, influx of Ca2+ via CaV1.2 channels mediates excitation-contraction coupling, controls the action potential duration and regulates gene expression [118]. Dysregulation of the CaV1.2 activity, subcellular localization or surface density in cardiomyocytes can result in cardiac arrhythmias and heart failure [119,120]. CaV1.2 isoforms are differentially expressed during heart development and possess different electrophysiological properties.…”

Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias

“…It is an autosomal-dominant disease with five identified causative genes, including three that encode for K + channels (KCNH2, KCNQ1, and KCNJ2) and two that encode for subunits of the L-type Ca 2+ channels (CACNA1C and CACNB2). [49][50][51] Mutations in the Ca V 1.2 genes CACNA1C and CACNB2b have also been associated with both idiopathic ventricular fibrillation and early repolarization syndrome. 43 A mutation in CACNA1D, which encodes Ca V 1.3, was identified in a Pakistani family with pronounced bradycardia resulting from nonconducting Ca V 1.3 channels.…”