| Voltage-gated calcium channels (VGCCs) convert electrical activity into calcium (Ca2+) signals that regulate cellular excitability, differentiation and connectivity. The magnitude and kinetics of Ca 2+ signals depend on the number of VGCCs at the plasma membrane, but little is known about the regulation of VGCC surface expression. We report that electrical activity causes internalization of the L-type Ca2+ channel (LTC) Cav1.2, and that this is mediated by binding to the tumor suppressor eIF3e/lnt6 (eukaryotic initiation factor 3 subunit e; p48). Using total internal reflection microscopy, we identify a population of Cav1.2 containing endosomes whose rapid trafficking is strongly regulated by intracellular Ca2+. Ca2+ elevations trigger internalization of surface channels and undocking of Ca v1.2 vesicles from the cell membrane leading to a decrease in the number of surface channels. We define a domain in the II-III loop of Cav1.2 that binds eIF3e and is essential for the activity-dependence of both channel internalization and endosomal trafficking. These findings provide a mechanism for activity-dependent internalization and trafficking of Cav1.2, and provide a tantalizing link between Ca2+ homeostasis and a mammalian oncogene. |
