α-Actinin-1 promotes activity of the L-type Ca2+ channel Cav1.2

Matthew Turner, David E. Anderson, Peter Bartels, Madeline Nieves-Cintron, Andrea M. Coleman, Peter B. Henderson, Kwun Nok Mimi Man, Pang Yen Tseng, Vladimir Yarov-Yarovoy, Donald M. Bers, Manuel F. Navedo, Mary C. Horne, James B. Ames, Johannes W. Hell

Research output: Contribution to journalArticle

Abstract

The L-type Ca2+ channel CaV1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of α-actinin to the IQ motif of CaV1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts CaV1.2 activity to its target sites. We solved separate NMR structures of the IQ motif (residues 1,646–1,664) bound to α-actinin-1 and to apo-calmodulin (apoCaM). The CaV1.2 K1647A and Y1649A mutations, which impair α-actinin-1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not α-actinin-1 binding, decreased single-channel open probability, gating charge movement, and its coupling to channel opening. Thus, α-actinin recruits CaV1.2 to defined surface regions and simultaneously boosts its open probability so that CaV1.2 is mostly active when appropriately localized.

Original languageEnglish (US)
Article numbere102622
JournalEMBO Journal
DOIs
StateAccepted/In press - Jan 1 2020

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Keywords

  • calmodulin
  • gating charge
  • IQ motif structure
  • open probability
  • surface expression

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Turner, M., Anderson, D. E., Bartels, P., Nieves-Cintron, M., Coleman, A. M., Henderson, P. B., Man, K. N. M., Tseng, P. Y., Yarov-Yarovoy, V., Bers, D. M., Navedo, M. F., Horne, M. C., Ames, J. B., & Hell, J. W. (Accepted/In press). α-Actinin-1 promotes activity of the L-type Ca2+ channel Cav1.2. EMBO Journal, [e102622]. https://doi.org/10.15252/embj.2019102622