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

摘要

Abstract 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.