Different subcellular populations of L-type Ca2+ channels exhibit unique regulation and functional roles in cardiomyocytes.

Influx of Ca(2+) through L-type Ca(2+) channels (LTCCs) contributes to numerous cellular processes in cardiomyocytes including excitation-contraction (EC) coupling, membrane excitability, and transcriptional regulation. Distinct subpopulations of LTCCs have been identified in cardiac myocytes, including those at dyadic junctions and within different plasma membrane microdomains such as lipid rafts and caveolae. These subpopulations of LTCCs exhibit regionally distinct functional properties and regulation, affording precise spatiotemporal modulation of L-type Ca(2+) current (I(Ca,L)). Different subcellular LTCC populations demonstrate variable rates of Ca(2+)-dependent inactivation and sometimes coupled gating of neighboring channels, which can lead to focal, persistent I(Ca,L). In addition, the assembly of spatially defined macromolecular signaling complexes permits compartmentalized regulation of I(Ca,L) by a variety of neurohormonal pathways. For example, β-adrenergic receptor subtypes signal to different LTCC subpopulations, with β(2)-adrenergic activation leading to enhanced I(Ca,L) through caveolar LTCCs and β(1)-adrenergic stimulation modulating LTCCs outside of caveolae. Disruptions in the normal subcellular targeting of LTCCs and associated signaling proteins may contribute to the pathophysiology of a variety of cardiac diseases including heart failure and certain arrhythmias. Further identifying the characteristic functional properties and array of regulatory molecules associated with specific LTCC subpopulations will provide a mechanistic framework to understand how LTCCs contribute to diverse cellular processes in normal and diseased myocardium. This article is part of a Special Issue entitled "Local Signaling in Myocytes".