Due to their essential biological roles, voltage-gated calcium channels (VGCCs) are regulated by a myriad of
molecules and mechanisms. Fifteen years ago, RGK proteins were discovered to bind the VGCC β subunit (Cavβ) and
potently inhibit high-voltage activated Ca2+ channels. RGKs (Rad, Rem, Rem2 and Gem/Kir) are a family of monomeric
small GTPases belonging to the superfamily of Ras GTPases. They exert dual inhibitory effects on VGCCs, decreasing
surface expression and suppressing surface channels through immobilization of the voltage sensor or reduction of channel
open probability. While Cavβ is required for all forms of RGK inhibition, not all inhibition is mediated by the RGK-Cavβ interaction. Some RGK proteins also interact directly with the pore-forming α1 subunit of some types of VGCCs (Cavα1).
Importantly, RGK proteins tonically inhibit VGCCs in native cells, regulating cardiac and neural functions. This minireview
summarizes the mechanisms, molecular determinants, and physiological impact of RGK inhibition of VGCCs.
Keywords: Action potential, calcium, cardiac, heart, GTP-ase, Ion channels, neurotransmitter release, regulation.
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