Designer genetically encoded voltage‐dependent calcium channel inhibitors inspired by RGK GTPases

High‐voltage‐activated calcium (Ca(V)1/Ca(V)2) channels translate action potentials into Ca(2+) influx in excitable cells to control essential biological processes that include; muscle contraction, synaptic transmission, hormone secretion and activity‐dependent regulation of gene expression. Modulation of Ca(V)1/Ca(V)2 channel activity is a powerful mechanism to regulate physiology, and there are a host of intracellular signalling molecules that tune different aspects of Ca(V) channel trafficking and gating for this purpose. Beyond normal physiological regulation, the diverse Ca(V) channel modulatory mechanisms may potentially be co‐opted or interfered with for therapeutic benefits. Ca(V)1/Ca(V)2 channels are potently inhibited by a four‐member sub‐family of Ras‐like GTPases known as RGK (Rad, Rem, Rem2, Gem/Kir) proteins. Understanding the mechanisms by which RGK proteins inhibit Ca(V)1/Ca(V)2 channels has led to the development of novel genetically encoded Ca(V) channel blockers with unique properties; including, chemo‐ and optogenetic control of channel activity, and blocking channels either on the basis of their subcellular localization or by targeting an auxiliary subunit. These genetically encoded Ca(V) channel inhibitors have outstanding utility as enabling research tools and potential therapeutics. [Image: see text]