SNX‐482: A Novel Class E Calcium Channel Antagonist from Tarantula Venom

ABSTRACT Calcium channels are represented by at least 9 distinct genes (calcium channel classes A‐I), corresponding to at least 5 functional and pharmacological “types” (L, N, P/Q, R and T). Selective L‐, N‐, and T‐type channel antagonists are either in clinical use or in late stage clinical trials, while antagonists of P/Q channels are known to be toxic. No selective ligand has been identified for the R‐type (class E), and its function and pharmacology are consequently, poorly understood. We review recent work on the discovery and initial characterization of SNX‐482, the first known selective antagonist of R‐type calcium channels. SNX‐482 is a 41 residue acidic peptide with three disulfide bonds that has been isolated from the venom of the African tarantula, Hysterocrates gigas. In cell‐based assays, it is a potent and selective inhibitor of the class E or R‐type calcium channel. SNX‐482 blocks some but not all native R‐type currents: it blocks an R‐type current in vertebrate neurohypophysis, but it does not block an R‐type current in cerebellar granule cells. The peptide blocks oxytocin but not vasopressin release, suggesting a possible utility for SNX‐482 as a neuroendocrine modulator. The peptide possesses antiseizure activity in several animal models of epilepsy, suggesting that class E antagonists may have pharmacological use in seizure disorders.