Dynamic L-type Ca(V)1.2 channel trafficking facilitates Ca(V)1.2 clustering and cooperative gating

L-type Ca(V)1.2 channels are key regulators of gene expression, cell excitability and muscle contraction. Ca(V)1.2 channels organize in clusters throughout the plasma membrane. This channel organization has been suggested to contribute to the concerted activation of adjacent Ca(V)1.2 channels (e.g. cooperative gating). Here, we tested the hypothesis that dynamic intracellular and perimembrane trafficking of Ca(V)1.2 channels is critical for formation and dissolution of functional channel clusters mediating cooperative gating. We found that Ca(V)1.2 moves in vesicular structures of circular and tubular shape with diverse intracellular and submembrane trafficking patterns. Both microtubules and actin filaments are required for dynamic movement of Ca(V)1.2 vesicles. These vesicles undergo constitutive homotypic fusion and fission events that sustain Ca(V)1.2 clustering, channel activity and cooperative gating. Our study suggests that Ca(V)1.2 clusters and activity can be modulated by diverse and unique intracellular and perimembrane vesicular dynamics to fine-tune Ca(2+) signals.