Interaction of pumiliotoxin B with an "alkaloid-binding domain" on the voltage-dependent sodium channel

F Gusovsky, WL Padgett, CR Creveling and JW Daly

Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.

The alkaloid pumiliotoxin B (PTX-B) "activates" voltage-dependent sodium channels in synaptoneurosomes and neuroblastoma cells. It appears that PTX-B activates sodium channels by interacting with a site that is allosterically coupled to other sites on the sodium channel, namely two scorpion toxin sites and the brevetoxin site. In guinea pig cortical synaptoneurosomes, alpha-scorpion toxin, beta-scorpion toxin, and brevetoxin induce a dose-dependent potentiation of PTX-B-induced 22Na+ influx. The synergism with beta-scorpion toxin differentiates PTX- B from the alkaloid veratridine, which induces an activation of sodium channels that is not affected by beta-scorpion toxin. PTX-B does not inhibit [3H]batrachotoxinin-A benzoate ([3H]BTX-B) binding to the alkaloid site on sodium channels. On the other hand, aconitine, which activates sodium channels and inhibits [3H]BTX-B binding, induces a 22Na+ influx that, like PTX-B-induced 22Na+ influx, is potentiated by alpha-scorpion toxin, beta-scorpion toxin, and brevetoxin. Inhibition of [3H]BTX-B binding by aconitine is reduced in the presence of PTX-B. Both a type I pyrethroid (allethrin) and a type II pyrethroid (fenvalerate) inhibit PTX-B- and PTX-B/alpha-scorpion toxin-mediated 22Na+ influx. Allethrin and fenvalerate also inhibit aconitine-mediated 22Na+ flux but not BTX-mediated 22Na+ influx. It is proposed that on the sodium channel there is an "alkaloid-binding domain" at which alkaloids exert stimulatory actions. However, depending on the region on the domain to which the binding occurs, different allosteric interactions with other sites can be observed. PTX-B is proposed to interact with a part of the alkaloid-binding domain that is shared by aconitine but not by batrachotoxin or veratridine, whereas aconitine interacts with a part of the domain shared by PTX-B and by batrachotoxin/veratridine.

Volume 42, Issue 6, pp. 1104-1108, 12/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				R. A. Saporito, H. M. Garraffo, M. A. Donnelly, A. L. Edwards, J. T. Longino, and J. W. Daly From the Cover: Formicine ants: An arthropod source for the pumiliotoxin alkaloids of dendrobatid poison frogs PNAS, May 25, 2004; 101(21): 8045 - 8050. [Abstract] [Full Text] [PDF]

				J. W. Daly, H. M. Garraffo, T. F. Spande, V. C. Clark, J. Ma, H. Ziffer, and J. F. Cover Jr. Evidence for an enantioselective pumiliotoxin 7-hydroxylase in dendrobatid poison frogs of the genus Dendrobates PNAS, September 16, 2003; 100(19): 11092 - 11097. [Abstract] [Full Text] [PDF]