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

The L-type Ca2+ channel Ca(V)1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of alpha-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 alpha-actinin-1 and to apo-calmodulin (apoCaM). The Ca(V)1.2 K1647A and Y1649A mutations, which impair alpha-actinin-1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not alpha-actinin-1 binding, decreased single-channel open probability, gating charge movement, and its coupling to channel opening. Thus, alpha-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.