Abstract
During cardiac excitation contraction coupling, the arrival of an action potential at the ventricular myocardium triggers voltage-dependent L-type Ca2+ (CaV1.2) 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 CaV1.2 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 CaV1.2 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 CaV1.2 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.
Highlights
Voltage-gated, L-type CaV 1.2 channels play an essential role in cardiac excitationcontraction (EC) coupling and can regulate cardiac gene expression
In heterologous and native systems interactions between CaV β and CaV α1c subunits lead to alterations in channel activation and inactivation as well as robust increases in surface expression and current density, likely due to an increased open probability and/or enhanced cell membrane localization of the channel complex [9,19,20,21,22,23]. This 1:1 stochiometric interaction between the subunits is thought to occur within the α-interaction domain (AID), located within the I-II pore loop of CaV α1c subunits [21,24], and small region of the guanylate kinase (GK) domain on CaV β, referred to as the alpha interaction domain (AID)-binding pocket (ABP) [16]
In a conference abstract we have yet to develop into a full manuscript [111], we reported that CaV 1.2 channel clusters are ~42% smaller in cardiac-specific Bridging integrator 1 (BIN1) heterozygous knockout (BIN1+/− ) mouse ventricular myocytes that have a less dense population of t-tubule micro-folds than WT counterparts [99]
Summary
Voltage-gated, L-type CaV 1.2 channels play an essential role in cardiac excitationcontraction (EC) coupling and can regulate cardiac gene expression. The number and activity of voltage-gated, L-type CaV 1.2 channels localized to specialized dyadic regions of the t-tubule sarcolemma, adjacent to ryanodine receptor (RyR2) clusters, dictates the degree of Ca2+ influx into cardiomyocytes and is a major determinant of the magnitude of ventricular contraction. CaV 1.2 channels localized to caveolae are thought to play a critical role in regulation of gene expression in a process known as excitation–transcription coupling. Targeting of CaV 1.2 channels to the appropriate membrane compartment is critical for their proper physiological function.
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