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α‐Actinin‐1 promotes activity of the L‐type Ca 2+ channel Ca v 1.2
Author(s) -
Turner Matthew,
Anderson David E,
Bartels Peter,
NievesCintron Madeline,
Coleman Andrea M,
Henderson Peter B,
Man Kwun Nok Mimi,
Tseng PangYen,
YarovYarovoy Vladimir,
Bers Donald M,
Navedo Manuel F,
Horne Mary C,
Ames James B,
Hell Johannes W
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102622
Subject(s) - biology , microbiology and biotechnology , type (biology) , biophysics , ecology
The L‐type Ca 2+ channel Ca V 1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of α‐actinin to the IQ motif of Ca V 1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi‐functional mechanism that restricts Ca V 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 Ca V 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 Ca V 1.2 to defined surface regions and simultaneously boosts its open probability so that Ca V 1.2 is mostly active when appropriately localized.