Dynamic L-type Ca1.2 channel trafficking facilitates Ca1.2 clustering and cooperative gating.

L-type Ca1.2 channels are key regulators of gene expression, cell excitability and muscle contraction. Ca1.2 channels organize in clusters throughout the plasma membrane. This channel organization has been suggested to contribute to the concerted activation of adjacent Ca1.2 channels (e.g. cooperative gating). Here, we tested the hypothesis that dynamic intracellular and perimembrane trafficking of Ca1.2 channels is critical for formation and dissolution of functional channel clusters mediating cooperative gating. We found that Ca1.2 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 Ca1.2 vesicles. These vesicles undergo constitutive homotypic fusion and fission events that sustain Ca1.2 clustering, channel activity and cooperative gating. Our study suggests that Ca1.2 clusters and activity can be modulated by diverse and unique intracellular and perimembrane vesicular dynamics to fine-tune Ca signals.