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 Ca²⁺ 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.