PT  - JOURNAL ARTICLE
AU  - Matthew Turner
AU  - David E. Anderson
AU  - Madeline Nieves-Cintron
AU  - Peter Bartels
AU  - Andrea M. Coleman
AU  - Peter B. Henderson
AU  - Kwun Nok Mimi Man
AU  - Vladimir Yarov-Yarovoy
AU  - Donald M. Bers
AU  - Manuel F. Navedo
AU  - Mary C. Horne
AU  - James B. Ames
AU  - Johannes W. Hell
TI  - α-Actinin-1 promotes activity of the L-type Ca<sup>2+</sup> Channel Ca<sub>V</sub>1.2
AID  - 10.1101/664102
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 664102
4099  - http://biorxiv.org/content/early/2019/06/10/664102.short
4100  - http://biorxiv.org/content/early/2019/06/10/664102.full
AB  - 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 1646-1664) 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.