Probing the Pathogenic Mechanisms Underlying CaV 1.2 Channelopathies

Abstract

Voltage gated Ca2+ channels are the main conduit for Ca2+ entry into most excitable cells, and the CaV1.2 L-type channel is among the most widespread, existing in cardiac, neuronal, and smooth muscle cells. These channels are precisely tuned to function within each of these systems, enabling the same channel type to coordinate neuronal excitability, vasoconstriction and cardiac excitation-contraction coupling. This tuning is accomplished in part by the nuances of channel gating and voltage dependence in each channel subtype, and by two major forms of feedback regulation: Ca2+ dependent inactivation (CDI) and voltage dependent inactivation (VDI). A growing number of genetic mutations in CaV1.2 are now recognized as the cause of severe cardiac and neuronal syndromes (channelopathies), which are frequently resistant to conventional treatment options. Biophysical studies have shown that these disease-causing mutations can often impact channel gating properties including CDI and VDI. However, as the number of known channelopathies continues to expand, so do the mechanistic differences among different mutations, resulting in increasing numbers of patients for which standard therapies are inadequate. Here, we aim to connect genetic mutations within CaV1.2 to specific effects on channel gating and regulation, in order to improve our understanding of the pathogenesis of these disorders. Moreover, these biophysical alterations likely underlie the lack of efficacy of calcium channel blockers in the treatment of these channelopathy patients. Thus, characterization of these channel deficits will increase our understanding of disease pathogenesis and redirect treatment strategies.