Competition between α-actinin and Ca²⁺-calmodulin controls surface retention of the L-type Ca²⁺ channel Ca(V)1.2.

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 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 α11.2 upon Ca²⁺ influx through L-type channels, but not through NMDAR, thereby triggering loss of Ca(V)1.2 from spines. Coexpression of a Ca²⁺-binding-deficient calmodulin mutant does not affect basal Ca(V)1.2 surface expression but inhibits its internalization upon Ca²⁺ influx. We conclude that α-actinin stabilizes Ca(V)1.2 at the plasma membrane and that its displacement by Ca²⁺-calmodulin triggers Ca²⁺-induced endocytosis of Ca(V)1.2, thus providing an important negative feedback mechanism for Ca²⁺ influx.