Voltage-gated calcium channels (VGCCs) convert electrical activity into calcium (Ca 2+ ) 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 Ca 2+ channel (LTC) Ca V 1.2 and that this is mediated by binding to the tumor suppressor eIF3e/Int6 (eukaryotic initiation factor 3 subunit e). Using total internal reflection microscopy, we identify a population of Ca V 1.2 containing endosomes whose rapid trafficking is strongly regulated by Ca 2+ . We define a domain in the II-III loop of Ca V 1.2 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 Ca V 1.2 and provide a tantalizing link between Ca 2+ homeostasis and a mammalian oncogene.