Mechanisms and Regulation of Cardiac Ca_V1.2 Trafficking

During cardiac excitation contraction coupling, the arrival of an action potential at the ventricular myocardium triggers voltage-dependent L-type Ca²⁺ (Ca_V1.2) channels in individual myocytes to open briefly. The level of this Ca²⁺ influx tunes the amplitude of Ca²⁺-induced Ca²⁺ release from ryanodine receptors (RyR2) on the junctional sarcoplasmic reticulum and thus the magnitude of the elevation in intracellular Ca²⁺ concentration and ultimately the downstream contraction. The number and activity of functional Ca_V1.2 channels at the t-tubule dyads dictates the amplitude of the Ca²⁺ influx. Trafficking of these channels and their auxiliary subunits to the cell surface is thus tightly controlled and regulated to ensure adequate sarcolemmal expression to sustain this critical process. To that end, recent discoveries have revealed the existence of internal reservoirs of preformed Ca_V1.2 channels that can be rapidly mobilized to enhance sarcolemmal expression in times of acute stress when hemodynamic and metabolic demand increases. In this review, we provide an overview of the current thinking on Ca_V1.2 channel trafficking dynamics in the heart. We highlight the numerous points of control including the biosynthetic pathway, the endosomal recycling pathway, ubiquitination, and lysosomal and proteasomal degradation pathways, and discuss the effects of β-adrenergic and angiotensin receptor signaling cascades on this process.