Rapid Turnover of the Cardiac L-Type Ca_V1.2 Channel by Endocytic Recycling Regulates Its Cell Surface Availability

Calcium entry through Ca_V1.2 L-type calcium channels regulates cardiac contractility. Here, we study the impact of exocytic and post-endocytic trafficking on cell surface channel abundance in cardiomyocytes. Single-molecule localization and confocal microscopy reveal an intracellular Ca_V1.2 pool tightly associated with microtubules from the perinuclear region to the cell periphery, and with actin filaments at the cell cortex. Channels newly inserted into the plasma membrane become internalized with an average time constant of 7.5 min and are sorted out to the Rab11a-recycling compartment. Ca_V1.2 recycling suffices for maintaining stable L-type current amplitudes over 20 hr independent of de novo channel transport along microtubules. Disruption of the actin cytoskeleton re-routes Ca_V1.2 from recycling toward lysosomal degradation. We identify endocytic recycling as essential for the homeostatic regulation of voltage-dependent calcium influx into cardiomyocytes. This mechanism provides the basis for a dynamic adjustment of the channel's surface availability and thus, of heart's contraction.