Competition between α-actinin and Ca2+-calmodulin controls surface retention of the L-type Ca2+ channel CaV1.2

Abstract

Regulation 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