Competition between α-actinin and Ca2+-Calmodulin Controls Surface Retention of the L-type Ca2+ Channel Cav1.2

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 a-actinin binds to the C-terminal surface targeting motif of alpha(1)1.2, the central pore-forming Ca(v)1.2 subunit, in order to foster its surface expression. Disruption of alpha-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 calnnodulin displaces a-actinin from their shared binding site on alpha(1)1.2 upon Ca2+ influx through L-type channel's, but not through NMDAR, thereby triggering loss of Ca(v)1.2 from spines. Coexpression of a Ca2+-(b)inding-deficient calmodulin mutant does not affect basal Ca(v)1.2 surface expression but inhibits its internalization upon Ca2+ influx. We conclude that alpha-actinin stabilizes Ca(v)1.2 at the plasma membrane and that its displacement by Ca2+-calnnodulin triggers Ca(2+-)induced endocytosis of Cav1.2, thus providing an important negative feedback mechanism for Ca2+ influx.