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Ca V 1/Ca V 2 channels, comprised of pore-forming α 1  and auxiliary (β,α 2 δ) subunits, control diverse biological responses in excitable cells. Molecules blocking Ca V 1/Ca V 2 channel currents ( I   Ca ) profoundly regulate physiology and have many therapeutic applications. Rad/Rem/Rem2/Gem GTPases (RGKs) strongly inhibit Ca V 1/Ca V 2 channels. Understanding how RGKs block  I   Ca  is critical for insights into their physiological function, and may provide design principles for developing novel Ca V 1/Ca V 2 channel inhibitors. The RGK binding sites within Ca V 1/Ca V 2 channel complexes responsible for  I   Ca  inhibition are ambiguous, and it is unclear whether there are mechanistic differences among distinct RGKs. All RGKs bind β subunits, but it is unknown if and how this interaction contributes to  I   Ca  inhibition. We investigated the role of RGK/β interaction in Rem inhibition of recombinant Ca V 1.2 channels, using a mutated β (β 2aTM ) selectively lacking RGK binding. Rem blocked β 2aTM -reconstituted channels (74% inhibition) less potently than channels containing wild-type β 2a  (96% inhibition), suggesting the prevalence of both β-binding-dependent and independent modes of inhibition. Two mechanistic signatures of Rem inhibition of Ca V 1.2 channels (decreased channel surface density and open probability), but not a third (reduced maximal gating charge), depended on Rem binding to β. We identified a novel Rem binding site in Ca V 1.2 α 1C  N-terminus that mediated β-binding-independent inhibition. The Ca V 2.2 α 1B  subunit lacks the Rem binding site in the N-terminus and displays a solely β-binding-dependent form of channel inhibition. Finally, we discovered an unexpected functional dichotomy amongst distinct RGKs— while Rem and Rad use both β-binding-dependent and independent mechanisms, Gem and Rem2 use only a β-binding-dependent method to inhibit Ca V 1.2 channels. The results provide new mechanistic perspectives, and reveal unexpected variations in determinants, underlying inhibition of Ca V 1.2/Ca V 2.2 channels by distinct RGK GTPases.

Distinct RGK GTPases Differentially Use α1- and Auxiliary β-Binding-Dependent Mechanisms to Inhibit CaV1.2/CaV2.2 Channels