Design and Applications of Genetically-Encoded Voltage-Dependent Calcium Channel Inhibitors

Ca²⁺ influx through high-voltage-gated Ca²⁺ channels (HVGCCs; Ca_V1/Ca_V2) is an exceptionally powerful and versatile signal that controls numerous cell and physiological functions including neurotransmission, muscle contraction, and regulation of gene expression. The impressive ability of a singular signal, Ca²⁺ influx, to have such a plethora of functional outcomes is enabled by: molecular diversity of HVGCC pore-forming α₁ and auxiliary subunits; organization of HVGCCs with extrinsic modulatory and effector protein to form discrete macromolecular complexes with unique properties; distinctive distribution of HVGCCs into separate subcellular compartments; and varying expression profiles of HVGCC isoforms among different tissues and organs. The capacity to block HVGCCs with selectivity and specificity with respect to the different levels of their organization is critical for fully understanding the scope of functional consequences of Ca²⁺ influx through them, and is also important for realizing their full potential as therapeutic targets. In this review, we discuss the gaps in the current landscape of small-molecule HVGCC blockers and how these may be addressed with designer genetically-encoded Ca²⁺ channel inhibitors (GECCIs) that draw inspiration from physiological protein inhibitors of HVGCCs.