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bioRxiv · 10.1101/664102

Alpha-Actinin-1 promotes activity of the L-type Ca2+ Channel CaV1.2

Turner, M.·Anderson, D.·Nieves-Cintron, M.·Bartels, P.·Coleman, A. M.·Henderson, P. B.·Man, K. N. M.·Yarov-Yarovoy, V.·Bers, D. M.·Navedo, M. F.·Horne, M. C.·Ames, J. B.·Hell, J. W.
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Abstract

The L-type Ca2+ channel CaV1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of -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 -actinin-1 and to apo-calmodulin (apoCaM). The CaV1.2 K1647A and Y1649A mutations, which impair -actinin-1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not -actinin-1 binding, decreased single channel open probability, gating charge movement, and its coupling to channel opening. Thus, -actinin recruits CaV1.2 to defined surface regions and simultaneously boosts its open probability so that CaV1.2 is mostly active when appropriately localized.

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Turner, M., Anderson, D., Nieves-Cintron, M., Bartels, P., Coleman, A. M., Henderson, P. B., Man, K. N. M., Yarov-Yarovoy, V., Bers, D. M., Navedo, M. F., Horne, M. C., Ames, J. B., Hell, J. W.. 2019-06-10. Alpha-Actinin-1 promotes activity of the L-type Ca2+ Channel CaV1.2. https://doi.org/10.1101/664102

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