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

Duane D. Hall, Shuiping Dai, Pang Yen Tseng, Zulfiqar Malik, Minh Nguyen, Lucas Matt, Katrin Schnizler, Andrew Shephard, Durga P. Mohapatra, Fuminori Tsuruta, Ricardo E. Dolmetsch, Carl J. Christel, Amy Lee, Alain Burette, Richard J. Weinberg, Johannes W Hell

Research output: Contribution to journalArticle

58 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)483-497
Number of pages15
JournalNeuron
Volume78
Issue number3
DOIs
StatePublished - May 8 2013

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Competition between α-actinin and Ca<sup>2+</sup>-calmodulin controls surface retention of the L-type Ca<sup>2+</sup> channel Ca<sub>V</sub>1.2'. Together they form a unique fingerprint.

  • Cite this

    Hall, D. D., Dai, S., Tseng, P. Y., Malik, Z., Nguyen, M., Matt, L., Schnizler, K., Shephard, A., Mohapatra, D. P., Tsuruta, F., Dolmetsch, R. E., Christel, C. J., Lee, A., Burette, A., Weinberg, R. J., & Hell, J. W. (2013). Competition between α-actinin and Ca2+-calmodulin controls surface retention of the L-type Ca2+ channel CaV1.2. Neuron, 78(3), 483-497. https://doi.org/10.1016/j.neuron.2013.02.032