Four polypeptide components of green mamba venom selectively block certain potassium channels in rat brain synaptosomes

CG Benishin, RG Sorensen, WE Brown, BK Krueger and MP Blaustein

Department of Physiology, University of Maryland School of Medicine, Baltimore 21201.

Venom from the green mamba (Dendroaspis angusticeps) blocked 86Rb efflux through voltage-gated K channels in rat brain synaptosomes. Crude venom inhibited both rapidly inactivating, 4-aminopyridine- sensitive K channels, and noninactivating, phencyclidine-sensitive, K channels. Fractionation of the venom by size exclusion chromatography and cation exchange high performance liquid chromatography yielded four 7000-dalton polypeptides (designated alpha-, beta-, gamma-, and delta- DaTX) that blocked synaptosome K channels. Two of these toxins, alpha- and delta-DaTX (10-100 nM), preferentially blocked the inactivating voltage-gated K channels. The other two toxins, beta- and gamma-DaTX, preferentially blocked the noninactivating voltage-gated K channels. The amino acid composition of these four toxins indicated that alpha- DaTX is identical to dendrotoxin [Br. J. Pharmacol. 77:153-161 (1982)] and toxin C13S2C3 [Hoppe-Seyler's Z. Physiol. Chem. 361:661-674 (1980)]; the composition and partial sequence analysis indicate that delta-DaTX is identical to toxin C13S1C3 [Hoppe-Seyler's Z. Physiol. Chem. 361:661-674 (1980)]. Beta- and gamma-DaTX have not previously been identified. Partial amino acid sequences of beta- and gamma-DaTX and the published sequences of alpha- and delta-DaTX reveal that the C- terminal segments of all four toxins are homologous. The C-terminal segments are also homologous with a number of nontoxic proteinase inhibitors. This raises the possibility that the N-terminal rather than the C-terminal regions are more likely responsible for the K channel blocking activity. The N-terminal portions of alpha- and delta-DaTX have some sequence homologies, but they have no obvious homologies with either beta- or gamma-DaTX. The finding of structurally similar peptide toxins with preferential activities toward different K channels may lead to the development of useful probes of K channel structure and may provide the means to distinguish among different K channels biochemically as well as physiologically.

Volume 34, Issue 2, pp. 152-159, 08/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

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