Competition between α-actinin and Ca2+-Calmodulin Controls Surface Retention of the L-type Ca2+ Channel CaV1.2

• α-actinin binding to CaV1.2 IQ region maintains CaV1.2 surface and spine localization
• Ca2+ influx via L channels, not NMDAR, displaces α-actinin from CaV1.2 via calmodulin
• Ca2+ influx via L channels results in loss of CaV1.2 from dendritic spines
• This Ca2+ influx causes rundown of L current by calmodulin-induced endocytosis

SummaryRegulation of neuronal excitability and cardiac excitation-contraction coupling requires the proper localization of L-type Ca2+ channels. We show that the actin-binding protein α-actinin binds to the C-terminal surface targeting motif of α11.2, the central pore-forming CaV1.2 subunit, in order to foster its surface expression. Disruption of α-actinin function by dominant-negative or small hairpin RNA constructs reduces CaV1.2 surface localization in human embryonic kidney 293 and neuronal cultures and dendritic spine localization in neurons. We demonstrate that calmodulin displaces α-actinin from their shared binding site on α11.2 upon Ca2+ influx through L-type channels, but not through NMDAR, thereby triggering loss of CaV1.2 from spines. Coexpression of a Ca2+-binding-deficient calmodulin mutant does not affect basal CaV1.2 surface expression but inhibits its internalization upon Ca2+ influx. We conclude that α-actinin stabilizes CaV1.2 at the plasma membrane and that its displacement by Ca2+-calmodulin triggers Ca2+-induced endocytosis of CaV1.2, thus providing an important negative feedback mechanism for Ca2+ influx.