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.

Keywords: Cardiac arrhythmia; L-type calcium channel; mutation.

Figure 1.

Predicted topology of Ca_V α₁ subunit with associated β₂ and α₂δ subunits shows the location of functional mutations. All mutations in α₁ subunit are derived from α_1C (Ca_V1.2), except one mutation G403_404ins is come from α_1D (Ca_V1.3). AID = α-subunit interaction domain; BID = β-subunit interaction domain; BrS = Brugada syndrome; CCD = cardiac conduction disease; ERS = early repolarization syndrome; GK = guanylate kinase; LQTS = long QT syndrome; SH3 = Src homology 3; SQTS = short QT syndrome; SNP = single nucleotide polymorphism; TS = Timothy syndrome.