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

Summary Regulation of neuronal excitability and cardiac excitation-contraction coupling requires the proper localization of L-type Ca 2+ channels. We show that the actin-binding protein α-actinin binds to the C-terminal surface targeting motif of α 1 1.2, the central pore-forming Ca V 1.2 subunit, in order to foster its surface expression. Disruption of α-actinin function by dominant-negative or small hairpin RNA constructs reduces Ca V 1.2 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 α 1 1.2 upon Ca 2+ influx through L-type channels, but not through NMDAR, thereby triggering loss of Ca V 1.2 from spines. Coexpression of a Ca 2+ -binding-deficient calmodulin mutant does not affect basal Ca V 1.2 surface expression but inhibits its internalization upon Ca 2+ influx. We conclude that α-actinin stabilizes Ca V 1.2 at the plasma membrane and that its displacement by Ca 2+ -calmodulin triggers Ca 2+ -induced endocytosis of Ca V 1.2, thus providing an important negative feedback mechanism for Ca 2+ influx.