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

• Published in: Neuron (Cambridge, Mass.) Vol. 78; no. 3; p. 483
• Main Authors: Hall, Duane D, Dai, Shuiping, Tseng, Pang-Yen, Malik, Zulfiqar, Nguyen, Minh, Matt, Lucas, Schnizler, Katrin, Shephard, Andrew, Mohapatra, Durga P, Tsuruta, Fuminori, Dolmetsch, Ricardo E, Christel, Carl J, Lee, Amy, Burette, Alain, Weinberg, Richard J, Hell, Johannes W
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Limited 08.05.2013
• Subjects: Cytoskeleton; Gene expression; Neurons; Rodents
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2013.02.032

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 -actinin binds to the C-terminal surface targeting motif of 11.2, the central pore-forming CaV1.2 subunit, in order to foster its surface expression. Disruption of -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 -actinin from their shared binding site on 11.2 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 -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.