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. 1992 May 1;99(5):699–720. doi: 10.1085/jgp.99.5.699

Mutually exclusive action of cationic veratridine and cevadine at an intracellular site of the cardiac sodium channel

PMCID: PMC2216617  PMID: 1318939

Abstract

Veratridine modification of Na current was examined in single dissociated ventricular myocytes from late-fetal rats by applying pulses to -30 mV for 50 ms every 2 or 5 s from a holding potential of - 100 mV (20 degrees C) and measuring amplitude, Itail, and time constant, tau tail, of the post-repolarization inward tail current induced by the alkaloid. Increasing the pH of a 30 microM veratridine superfusate from 7.3 to 8.3 (which increases the fraction of uncharged veratridine molecules from 0.5 to 5% while decreasing that of protonated molecules from 99.5 to 95%) increased Itail by a factor of 2.5 +/- 0.5 (mean +/- SEM; n = 3). Switching from 100 microM veratridine superfusate at pH 7.3 to 10 microM at pH 8.3 did not affect the size of Itail (n = 4). Intracellular (pipette) application of 100 microM veratridine at pH 7.3 or 8.3 produced small Itail's suggesting transmembrane loss of alkaloid. If this was compensated for by simultaneous extracellular application of 100 microM veratridine at a pH identical to intracellular pH, Itail (measured relative to the maximum amplitude induced by a combination of 100 microM veratridine and 1 microM BDF 9145 in the same cell) at pHi 7.3 did not significantly differ from that at pHi 8.3 (84 +/- 4 vs. 70 +/- 6%; n = 3 each). Results from six control cells and five cells subjected to extra- and/or intracellularly increased viscosity by the addition of 0.5 or 1 molal sucrose showed that increasing intracellular viscosity 1.6- and 2.5-fold increased tau tail 1.5- and 2.3-fold, respectively, while a selective 2.5-fold increase of extracellular viscosity did not significantly affect tau tail.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Barnes S., Hille B. Veratridine modifies open sodium channels. J Gen Physiol. 1988 Mar;91(3):421–443. doi: 10.1085/jgp.91.3.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Cribbs L. L., Satin J., Fozzard H. A., Rogart R. B. Functional expression of the rat heart I Na+ channel isoform. Demonstration of properties characteristic of native cardiac Na+ channels. FEBS Lett. 1990 Nov 26;275(1-2):195–200. doi: 10.1016/0014-5793(90)81470-9. [DOI] [PubMed] [Google Scholar]
  4. Hille B. Charges and potentials at the nerve surface. Divalent ions and pH. J Gen Physiol. 1968 Feb;51(2):221–236. doi: 10.1085/jgp.51.2.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hille B., Leibowitz M. D., Sutro J. B., Schwarz J. R., Holan G. State-dependent modification of sodium channels by lipid-soluble agonists. Soc Gen Physiol Ser. 1987;41:109–124. [PubMed] [Google Scholar]
  6. Honerjäger P., Frelin C., Lazdunski M. Actions, interactions, and apparent affinities of various ceveratrum alkaloids at sodium channels of cultured neuroblastoma and cardiac cells. Naunyn Schmiedebergs Arch Pharmacol. 1982 Nov;321(2):123–129. doi: 10.1007/BF00518479. [DOI] [PubMed] [Google Scholar]
  7. Howe J. R., Ritchie J. M. On the active form of 4-aminopyridine: block of K+ currents in rabbit Schwann cells. J Physiol. 1991 Feb;433:183–205. doi: 10.1113/jphysiol.1991.sp018421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kallen R. G., Sheng Z. H., Yang J., Chen L. Q., Rogart R. B., Barchi R. L. Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle. Neuron. 1990 Feb;4(2):233–242. doi: 10.1016/0896-6273(90)90098-z. [DOI] [PubMed] [Google Scholar]
  9. Leibowitz M. D., Schwarz J. R., Holan G., Hille B. Electrophysiological comparison of insecticide and alkaloid agonists of Na channels. J Gen Physiol. 1987 Jul;90(1):75–93. doi: 10.1085/jgp.90.1.75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. McKinney L. C., Chakraverty S., De Weer P. Purification, solubility, and pKa of veratridine. Anal Biochem. 1986 Feb 15;153(1):33–38. doi: 10.1016/0003-2697(86)90056-4. [DOI] [PubMed] [Google Scholar]
  11. Miller C. Diffusion-controlled binding of a peptide neurotoxin to its K+ channel receptor. Biochemistry. 1990 Jun 5;29(22):5320–5325. doi: 10.1021/bi00474a016. [DOI] [PubMed] [Google Scholar]
  12. Moorman J. R., Kirsch G. E., Brown A. M., Joho R. H. Changes in sodium channel gating produced by point mutations in a cytoplasmic linker. Science. 1990 Nov 2;250(4981):688–691. doi: 10.1126/science.2173138. [DOI] [PubMed] [Google Scholar]
  13. Narahashi T., Deguchi T., Albuquerque E. X. Effects of batrachotoxin on nerve membrane potential and conductances. Nat New Biol. 1971 Feb 17;229(7):221–222. doi: 10.1038/newbio229221b0. [DOI] [PubMed] [Google Scholar]
  14. Negulyaev YuA, Vedernikova E. A., Savokhina G. A. Aconitine-induced modification of single sodium channels in neuroblastoma cell membrane. Gen Physiol Biophys. 1990 Apr;9(2):167–176. [PubMed] [Google Scholar]
  15. Noda M., Suzuki H., Numa S., Stühmer W. A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II. FEBS Lett. 1989 Dec 18;259(1):213–216. doi: 10.1016/0014-5793(89)81531-5. [DOI] [PubMed] [Google Scholar]
  16. Rando T. A. Rapid and slow gating of veratridine-modified sodium channels in frog myelinated nerve. J Gen Physiol. 1989 Jan;93(1):43–65. doi: 10.1085/jgp.93.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rogart R. B., Cribbs L. L., Muglia L. K., Kephart D. D., Kaiser M. W. Molecular cloning of a putative tetrodotoxin-resistant rat heart Na+ channel isoform. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8170–8174. doi: 10.1073/pnas.86.20.8170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. SHANES A. M., GERSHFELD N. L. Interactions of veratrum alkaloids, procaine, and calcium with monolayers of stearic acid and their implications for pharmacological action. J Gen Physiol. 1960 Nov;44:345–363. doi: 10.1085/jgp.44.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. SHANES A. M. The ultraviolet spectra and neurophysiological effects of "veratrine" alkaloids. J Pharmacol Exp Ther. 1952 Jun;105(2):216–231. [PubMed] [Google Scholar]
  20. Schild L., Moczydlowski E. Competitive binding interaction between Zn2+ and saxitoxin in cardiac Na+ channels. Evidence for a sulfhydryl group in the Zn2+/saxitoxin binding site. Biophys J. 1991 Mar;59(3):523–537. doi: 10.1016/S0006-3495(91)82269-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Schurr J. M. The role of diffusion in bimolecular solution kinetics. Biophys J. 1970 Aug;10(8):700–716. doi: 10.1016/S0006-3495(70)86330-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Seyama I., Narahashi T. Increase in sodium permeability of squid axon membranes by -dihydrograyanotoxin II. J Pharmacol Exp Ther. 1973 Feb;184(2):299–307. [PubMed] [Google Scholar]
  23. Seyama I., Yamada K., Kato R., Masutani T., Hamada M. Grayanotoxin opens Na channels from inside the squid axonal membrane. Biophys J. 1988 Feb;53(2):271–274. doi: 10.1016/S0006-3495(88)83088-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Stühmer W., Conti F., Suzuki H., Wang X. D., Noda M., Yahagi N., Kubo H., Numa S. Structural parts involved in activation and inactivation of the sodium channel. Nature. 1989 Jun 22;339(6226):597–603. doi: 10.1038/339597a0. [DOI] [PubMed] [Google Scholar]
  25. Sutro J. B. Kinetics of veratridine action on Na channels of skeletal muscle. J Gen Physiol. 1986 Jan;87(1):1–24. doi: 10.1085/jgp.87.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tejedor F. J., Catterall W. A. Site of covalent attachment of alpha-scorpion toxin derivatives in domain I of the sodium channel alpha subunit. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8742–8746. doi: 10.1073/pnas.85.22.8742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Thomsen W. J., Catterall W. A. Localization of the receptor site for alpha-scorpion toxins by antibody mapping: implications for sodium channel topology. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10161–10165. doi: 10.1073/pnas.86.24.10161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ulbricht W. Rate of veratridine action on the nodal membrane. I. Fast phase determined during sustained depolarization in the voltage clamp. Pflugers Arch. 1972;336(3):187–199. doi: 10.1007/BF00590043. [DOI] [PubMed] [Google Scholar]
  29. Ulbricht W. The effect of veratridine on excitable membranes of nerve and muscle. Ergeb Physiol. 1969;61:18–71. doi: 10.1007/BFb0111446. [DOI] [PubMed] [Google Scholar]
  30. Vassilev P. M., Scheuer T., Catterall W. A. Identification of an intracellular peptide segment involved in sodium channel inactivation. Science. 1988 Sep 23;241(4873):1658–1661. doi: 10.1126/science.241.4873.1658. [DOI] [PubMed] [Google Scholar]
  31. Wang G., Dugas M., Armah B. I., Honerjäger P. Sodium channel comodification with full activator reveals veratridine reaction dynamics. Mol Pharmacol. 1990 Feb;37(2):144–148. [PubMed] [Google Scholar]
  32. Warnick J. E., Albuquerque E. X., Onur R., Jansson S. E., Daly J., Tokuyama T., Witkop B. The pharmacology of batrachotoxin. VII. Structure-activity relationships and the effects of pH. J Pharmacol Exp Ther. 1975 Apr;193(1):232–245. [PubMed] [Google Scholar]
  33. Zong X. G., Dugas M., Honerjäger P. Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells. J Gen Physiol. 1992 May;99(5):683–697. doi: 10.1085/jgp.99.5.683. [DOI] [PMC free article] [PubMed] [Google Scholar]

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