Different Subcellular Populations of L-type Ca2+ Channels Exhibit Unique Regulation and Functional Roles in Cardiomyocytes

摘要

Influx of Ca²⁺ through L-type Ca²⁺ 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 Ca²⁺ current (ICa,L). Different subcellular LTCC populations demonstrate variable rates of Ca²⁺-dependent inactivation and sometimes coupled gating of neighboring channels, which can lead to focal, persistent ICa,L. In addition, the assembly of spatially defined macromolecular signaling complexes permits compartmentalized regulation of ICa,L by a variety of neurohormonal pathways. For example, β-adrenergic receptor subtypes signal to different LTCC subpopulations, with β2-adrenergic activation leading to enhanced ICa,L through caveolar LTCCs and β1-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.