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α-Actinin-1 promotes activity of the L-type Ca2+ channel Cav 1.2.

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

The L-type Ca2+ channel CaV 1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of α-actinin to the IQ motif of CaV 1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts CaV 1.2 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 CaV 1.2 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 CaV 1.2 to defined surface regions and simultaneously boosts its open probability so that CaV 1.2 is mostly active when appropriately localized.

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