Calcium Channel Mutations in Cardiac Arrhythmia Syndromes

Abstract

Voltage gated calcium channels are essential for cardiac physiology by serving as sarcolemma- restricted gatekeepers for calcium in cardiac myocytes. Activation of the L-type voltagegated calcium channel provides the calcium entry required for excitation-contraction coupling and contributes to the plateau phase of the cardiac action potential. Given these critical physiological roles, subtle disturbances in L-type channel function can lead to fatal cardiac arrhythmias. Indeed, numerous human arrhythmia syndromes have been linked to mutations in the L-type channel leading to gain-of-function or loss-of-function mutations. In this review, we discuss the current state of knowledge regarding these mutations present in Timothy Syndrome, Long and Short QT Syndromes, Brugada Syndrome and Early Repolarization Syndrome. We discuss the pathological consequences of the mutations, the biophysical effects of the mutations on the channel as well as possible therapeutic considerations and challenges for future studies.

Figure 1

Schematic of the L-type cardiac calcium channel showing missense mutation associated with loss of function, contributing to BrS and/or ERS and/or SQTS (green), those associated with a gain of function with extracardiac manifestations contributing to Timothy syndrome and Timothy-like syndromes (red), and gain of function mutations without extracardiac manifestations (rose). The auxiliary subunits Ca_Vβ2 and α2δ1 are also shown, and the locations of loss of function mutations contributing to BrS and/or ERS and/or SQTS and indicated (green dots). For clarity, the mutations in the auxiliary subunits are not identified by amino acid.