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. 1988 Feb;85(4):1272–1276. doi: 10.1073/pnas.85.4.1272

Pumiliotoxin B binds to a site on the voltage-dependent sodium channel that is allosterically coupled to other binding sites.

F Gusovsky 1, D P Rossignol 1, E T McNeal 1, J W Daly 1
PMCID: PMC279749  PMID: 2448797

Abstract

Pumiliotoxin B (PTX-B), an alkaloid that has cardiotonic and myotonic activity, increases sodium influx in guinea pig cerebral cortical synaptoneurosomes. In the presence of scorpion venom (Leiurus) or purified alpha-scorpion toxin, the PTX-B-induced sodium influx is enhanced severalfold. PTX-B alone has no effect on sodium flux in N18 neuroblastoma cells but, in the presence of alpha-scorpion toxin, stimulation of sodium influx by PTX-B reaches levels comparable to that attained with the sodium channel activator veratridine. In neuroblastoma LV9 cells, a variant mutant that lacks sodium channels, neither veratridine nor PTX-B induces sodium fluxes in either the presence or absence of alpha-scorpion toxin. In synaptoneurosomes and in N18 cells, the sodium influx induced by the combination of PTX-B and alpha-scorpion toxin is inhibited by tetrodotoxin and local anesthetics. PTX-B does not interact with two of the known toxin sites on the sodium channel, as evidenced by a lack of effect on binding of [3H]saxitoxin or [3H]batrachotoxinin A benzoate to brain synaptoneurosomes. Synergistic effects on sodium influx with alpha-scorpion toxin, beta-scorpion toxin, and brevetoxin indicate that PTX-B does not interact directly with three other toxin sites on the sodium channel. Thus, PTX-B appears to activate sodium influx by interacting with yet another site on the voltage-dependent sodium channel, a site that is coupled allosterically to sites for alpha-scorpion toxin, beta-scorpion toxin, and brevetoxin.

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Selected References

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  1. Albuquerque E. X., Warnick J. E., Maleque M. A., Kauffman F. C., Tamburini R., Nimit Y., Daly J. W. The pharmacology of pumiliotoxin-B. I. Interaction with calcium sites in the sarcoplasmic reticulum of skeletal muscle. Mol Pharmacol. 1981 May;19(3):411–424. [PubMed] [Google Scholar]
  2. Bablito J., Jover E., Couraud F. Activation of the voltage-sensitive sodium channel by a beta-scorpion toxin in rat brain nerve-ending particles. J Neurochem. 1986 Jun;46(6):1763–1770. doi: 10.1111/j.1471-4159.1986.tb08494.x. [DOI] [PubMed] [Google Scholar]
  3. Catterall W. A. Activation of the action potential Na+ ionophore by neurotoxins. An allosteric model. J Biol Chem. 1977 Dec 10;252(23):8669–8676. [PubMed] [Google Scholar]
  4. Catterall W. A., Gainer M. Interaction of brevetoxin A with a new receptor site on the sodium channel. Toxicon. 1985;23(3):497–504. doi: 10.1016/0041-0101(85)90034-0. [DOI] [PubMed] [Google Scholar]
  5. Catterall W. A., Morrow C. S., Daly J. W., Brown G. B. Binding of batrachotoxinin A 20-alpha-benzoate to a receptor site associated with sodium channels in synaptic nerve ending particles. J Biol Chem. 1981 Sep 10;256(17):8922–8927. [PubMed] [Google Scholar]
  6. Catterall W. A. Purification of a toxic protein from scorpion venom which activates the action potential Na+ ionophore. J Biol Chem. 1976 Sep 25;251(18):5528–5536. [PubMed] [Google Scholar]
  7. Catterall W. A. The molecular basis of neuronal excitability. Science. 1984 Feb 17;223(4637):653–661. doi: 10.1126/science.6320365. [DOI] [PubMed] [Google Scholar]
  8. Couraud F., Jover E., Dubois J. M., Rochat H. Two types of scorpion receptor sites, one related to the activation, the other to the inactivation of the action potential sodium channel. Toxicon. 1982;20(1):9–16. doi: 10.1016/0041-0101(82)90138-6. [DOI] [PubMed] [Google Scholar]
  9. Creveling C. R., McNeal E. T., Daly J. W., Brown G. B. Batrachotoxin-induced depolarization and [3H]batrachotoxinin-a 20 alpha-benzoate binding in a vesicular preparation from guinea pig cerebral cortex. Mol Pharmacol. 1983 Mar;23(2):350–358. [PubMed] [Google Scholar]
  10. Daly J. W., McNeal E. T., Overman L. E., Ellison D. H. A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid A new class of A new class of cardiotonic agents: structure-activity correlations for natural and synthetic analogues of the alkaloid pumiliotoxin B (8-hydroxy-8-methyl-6-alkylidene-1-azabicyclo[4.3.0]nonanes). J Med Chem. 1985 Apr;28(4):482–486. doi: 10.1021/jm00382a017. [DOI] [PubMed] [Google Scholar]
  11. Gusovsky F., Hollingsworth E. B., Daly J. W. Regulation of phosphatidylinositol turnover in brain synaptoneurosomes: stimulatory effects of agents that enhance influx of sodium ions. Proc Natl Acad Sci U S A. 1986 May;83(9):3003–3007. doi: 10.1073/pnas.83.9.3003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hollingsworth E. B., McNeal E. T., Burton J. L., Williams R. J., Daly J. W., Creveling C. R. Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3':5'-monophosphate-generating systems, receptors, and enzymes. J Neurosci. 1985 Aug;5(8):2240–2253. doi: 10.1523/JNEUROSCI.05-08-02240.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jacques Y., Romey G., Cavey M. T., Kartalovski B., Lazdunski M. Interaction of pyrethroids with the Na+ channel in mammalian neuronal cells in culture. Biochim Biophys Acta. 1980 Aug 14;600(3):882–897. doi: 10.1016/0005-2736(80)90491-5. [DOI] [PubMed] [Google Scholar]
  14. Mensah-Dwumah M., Daly J. W. Pharmacological activity of alkaloids from poison-dart frogs (Dendrobatidae). Toxicon. 1978;16(2):189–194. doi: 10.1016/0041-0101(78)90037-5. [DOI] [PubMed] [Google Scholar]
  15. Peterson G. L. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977 Dec;83(2):346–356. doi: 10.1016/0003-2697(77)90043-4. [DOI] [PubMed] [Google Scholar]
  16. Sharkey R. G., Jover E., Couraud F., Baden D. G., Catterall W. A. Allosteric modulation of neurotoxin binding to voltage-sensitive sodium channels by Ptychodiscus brevis toxin 2. Mol Pharmacol. 1987 Mar;31(3):273–278. [PubMed] [Google Scholar]
  17. Tamkun M. M., Catterall W. A. Ion flux studies of voltage-sensitive sodium channels in synaptic nerve-ending particles. Mol Pharmacol. 1981 Jan;19(1):78–86. [PubMed] [Google Scholar]

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