CNS Drug Reviews Vol. 6, No. 2, pp. 153–173 © 2000 Neva Press, Branford, Connecticut

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

Robert Newcomb,† Xiao-hua Chen,† Robin Dean,† Govindin Dayanithi,+ Ruth Cong,† Balazs Szoke,† Jose Lemos,* Scott Bowersox,† and George Miljanich†

†Elan Pharmaceuticals Inc., Menlo Park, CA, USA; *Department of Physiology, University of Massachusetts, Amherst, MA, USA; +CNRS Montpellier, France

Key Words: Calcium—Class E calcium channel—Epilepsy—Neurohypophysis—Oxytocin— Premature labor—R-type calcium channel—SNX-482—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 char- acterization 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 pharma- cological use in seizure disorders.