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Antagonism by Local Anesthetics of Sodium Channel Activators in the Presence of Scorpion Toxins: Two Mechanisms for Competitive Inhibition

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Abstract

1. The interaction of veratridine (VTD), a Na+ channel activator, scorpion α-toxin (LQ), an open state Na+ channel stabilizer, and the local anesthetic, lidocaine (LID), a channel inhibitor, at the neuronal sodium channel was assessed by measuring VTD-dependent slow depolarizations of frog sciatic nerve using the sucrose-gap method.

2. The slow depolarizing action of veratridine was potentiated more than 10-fold by the peptide LQ toxin, whereas its competitive inhibition by lidocaine was unchanged by LQ.

3. We conclude that the antagonism between VTD and a LID molecule during slow depolarization is allosteric, involving a trapping of the Na+ channel by LID in the inactivated state that has a very low affinity for VTD.

4. The binding of VTD to the open state of the channel, which is stabilized by LQ, may be inhibited by orthosteric competition at overlapping sites since both LID and VTD bind avidly and rapidly to open channels.

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REFERENCES

  • Armstrong, C. M., and Bezanilla, F. (1974). Charge movement associated with the opening and closing of the activation gates of the Na channels. J. Gen. Physiol. 63:533–552.

    Google Scholar 

  • Barnes, S., and Hille, B. (1988). Veratridine modifies open sodium channels. J. Gen. Physiol. 91:421–443.

    Google Scholar 

  • Bean, B. P., Cohen, C. J., and Tsien, R. W. (1983). Lidocaine block of cardiac sodium channels. J. Gen. Physiol. 81:613–642.

    Google Scholar 

  • Cahalan, M. D., and Almers, W. (1979). Interactions between quaternary lidocaine, the sodium channel gates and tetrodotoxin. Biophys. J. 27:39–56.

    Google Scholar 

  • Catterall, W. A. (1977). Activation of the action potential Na+ ionophore by neurotoxins. An allosteric model. J. Biol. Chem. 252:8669–8676.

    Google Scholar 

  • Catterall, W. A. (1979). Binding of scorpion toxin to receptor site associated with sodium channels in frog muscle. Correlation of voltage-dependent binding with activation. J. Gen. Physiol. 74:357–391.

    Google Scholar 

  • Catterall, W. A. (1980). Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Ann. Rev. Pharmacol. Toxicol. 20:15–43.

    Google Scholar 

  • Chernoff, D. M. (1990). Kinetic analysis of phasic inhibition of neuronal sodium currents by lidocaine and bupivacaine. Biophys. J. 58:53–68.

    Google Scholar 

  • Chernoff, D. M., and Strichartz, G. R. (1990). Kinetics of local anesthetic inhibition of neuronal sodium currents: pH-and hydrophobicity dependence. Biophys. J. 58:69–81.

    Google Scholar 

  • Courtney, K. R. (1975). Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA968. J. Pharmacol. Exp. Ther. 195:225–236.

    Google Scholar 

  • French, R. J., Zamponi, G. W., and Sierralta, I. E. (1998). Molecular and kinetic determinants of local anaesthetic action on sodium channels. Toxicol. Lett. 100/101:247–254.

    Google Scholar 

  • Hahin, R., and Strichartz, G. R. (1981). Effects of deuterium oxide on the rate and dissociation constants for saxitoxin and tetrodotoxin action. J. Gen. Physiol. 78:113–129.

    Google Scholar 

  • Hille, B. (1977). Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69:497–515.

    Google Scholar 

  • Hill, R. J., Duff, H. J., and Sheldon, R. S. (1989). Class I antiarrhythmic drug receptor: Biochemical evidence for state-specific interaction with quinidine and lidocaine. Mol. Pharmacol. 36:150–159.

    Google Scholar 

  • Hondeghem, L. M., and Katzung, B. G. (1977). Time and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim. Biophys. Acta 472:373–398.

    Google Scholar 

  • Keynes, R. D., and Rojas, E. (1974). Kinetics and steady state properties of the charged system controlling sodium conductance in the squid giant axon. J. Physiol. (Lond.) 239:393–434.

    Google Scholar 

  • Khodorov, B. I., Shishkova, L., Peganov, E., and Revenko, S. (1976). Inhibition of sodium currents in frog Ranvier node treated with local anesthetics: Role of slow sodium inactivation. Biochim. Biophys. Acta. 433:409–435.

    Google Scholar 

  • LeeSon, S., Wang, G. K., Concus Crill, A. E., and Strichartz, G. (1992). Stereoselective inhibition of neuronal sodium channels by local anesthetics: Evidence for two sites of action? Anesthesiology 77:324–335.

    Google Scholar 

  • Leibowitz, M. D., Sutro, J. B., and Hille, B. (1986). Voltage-dependent gating of veratridine modified Na channels. J. Gen. Physiol. 87:25–46.

    Google Scholar 

  • Linford, N. J., Cantrell, A. R., Qu, Y., Scheuer, T., and Catterall, W. A. (1998). Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel. Proc. Natl. Acad. Sci. U.S.A. 95:13947–13952.

    Google Scholar 

  • McKinney, L. C., Chakraverty, S., and DeWeer, P. (1986). Purification, solubility and pKa of veratridine. Anal. Biochem. 153:33–86.

    Google Scholar 

  • Mozhayeva, G. N., Naumov, A. P., Nosyreva, E. D., and Grishin, E. V. (1980). Potential-dependent interaction of toxin from venom of the scorpion Buthus eupeus with sodium channels in myelinated fibre: Voltage clamp experiments. Biochim. et Biophys. Acta 597:587–602.

    Google Scholar 

  • Nau, C., Wang, S.-Y., Strichartz, G. R., and Wang, G. K. (1999). Point mutations at N434 in D1-S6 of μ1 Na+ channels modulate binding affinity and stereoselectivity of local anesthetic enantiomers. Mol. Pharmacol. 56:404–413.

    Google Scholar 

  • Postma, S. W., and Catterall, W. A. (1984). Inhibition of binding of 3H-batrachotoxin A 20 α-benzoate to sodium channels by local anesthetics. Mol. Pharmacol. 25:219–227.

    Google Scholar 

  • Ragsdale, D. S., McPhee, J. C., Scheuer, T., and Catterall, W. A. (1994). Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 265:1724–1728.

    Google Scholar 

  • Ragsdale, D. S., McPhee, D. S., Scheuer, J. C., and Catterall, W. A. (1996). Common molecular determinants of local anesthetic, antiarrhythmic and anticonvulsant block of voltage gated Na+ channels. Proc. Natl. Acad. Sci. U.S.A. 93:9270–9275.

    Google Scholar 

  • Rando, T. A. (1989). Rapid and slow gating of veratridine-modified sodium channels in frog myelinated nerve. J. Gen. Physiol. 93:43–65.

    Google Scholar 

  • Rando, T. A., Wang, G. K., and Strichartz, G. R. (1986). The interaction of alkaloid neurotoxins, batrachotoxin and veratridine, with the gating processes of neuronal sodium channels. Mol. Pharmacol. 29:467–477.

    Google Scholar 

  • Rogers, J. C., Qu, Y., Tanada, T. N., Scheuer, T., and Catterall, W. A. (1996). Molecular determinants of high affinity binding of α-scorpion toxin and sea anemone toxin in the S3–S4 extracellular loop in domain IV of the Na+ channel α subunit. J. Biol. Chem. 271:15950–15962.

    Google Scholar 

  • Schwarz, W., Palade, P. T., and Hille, B. (1977). Local anesthetics: Effects of pH on use-dependent block of sodium channels in frog. Biophys. J. 20:343–368.

    Google Scholar 

  • Sheldon, R. S., Cannon, N. J., and Duff, H. J. (1991). A receptor for type I antiarrhythmic drugs associated with cardiac sodium channels. Circ. Res. 61:492–497.

    Google Scholar 

  • Sheldon, R. S., Hill, R. J., Taouis, M., and Wilson, L. M. (1987). Aminoalkyl structural requirements for interaction of lidocaine with class 1 antiarrhythmic drug receptor on rat cardiac myocytes. Mol. Pharmacol. 39:609–614.

    Google Scholar 

  • Starmer, C. F., and Grant, A. O. (1985). Phasic ion channel blockade: A kinetic model and parameter estimation procedure. Mol. Pharmacol. 283:348–356.

    Google Scholar 

  • Strichartz, G., Rando, T. A., and Wang, G. K. (1987). An integrated view of the molecular toxinology of sodium channel gaiting in excitable cells. Ann. Rev. Neurosci. 10:237–267.

    Google Scholar 

  • Strichartz, G., and Wang, G. K. (1986). Rapid voltage-dependent dissociation of scorpion alpha-toxins coupled to Na channel inactivation in amphibian myelinated nerve. J. Gen. Physiol. 88:413–435.

    Google Scholar 

  • Sutro, J. B. (1986). Kinetics of veratridine action on Na channels of skeletal muscle. J. Gen. Physiol. 87:1–24.

    Google Scholar 

  • Ulbricht, W., and Stoye-Herzog, M. (1984). Distinctly different rates of benzocaine action on sodium channels of Ranvier nodes kept open by chloramne-T and veratridine. Pflugers Arch. 402:439–445.

    Google Scholar 

  • Wang, G. K. (1990). Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels. J. Gen. Physiol. 96:1105–1127.

    Google Scholar 

  • Wang, S.-Y., Barile, M., and Wang, G. K. (2001). Disparate role of Na+ channel D2-S6 residues in batrachotoxin and local anesthetic action. Mol. Pharmacol. 59:1100–1107.

    Google Scholar 

  • Wang, S.-Y., Nau, C., and Wang, G. K. (2000). Residues in Na+ channel D3-S6 segment modulate both batrachotoxin and local anesthetic affinities. Biophys. J. 79:1379–1387.

    Google Scholar 

  • Wang, G. K., Quan, C., and Wang, S.-Y. (1998). Local anesthetic block of batrachotoxin-resistant muscle Na+ channels. Mol. Pharmacol. 54:389–396.

    Google Scholar 

  • Wang, G. K., Simon, R., Bell, D., and Wany, S. Y. (1993). Structural determinants of quarternary ammonium blockers for BTX-modified Na+ channels. Mol. Pharmacol. 44:667–676.

    Google Scholar 

  • Wang, G. K., and Strichartz, G. (1983). Purification and physiological characterization of isotoxins from venoms of the scorpion Centruroids sculpturatus and Leiurus quinquestriatus. Mol. Pharmacol. 341:62p.

  • Wang, G. K., and Wang, S. Y. (2003). Veratridine block of rat skeletal muscle Nav1.4 sodium channels in the inner vestibule. J. Physiol. 548:667–675.

    Google Scholar 

  • Willow, M., and Catterall, W. A. (1982). Inhibition of binding of [3H] batrachotoxin a 20-α-benzoate to sodium channels by anticonvulsant drugs diphenylhydantoin and carbamazappine. Mol. Pharmacol. 22:627–635.

    Google Scholar 

  • Willow, M., Gonoi, T., Postma, S. W., and Catterall, W. A. (1986). Inhibition of voltage-sensitive sodium channels by local anesthetics and anticonvulsants: A biochemical and electrophysiological analysis. In Roth, S. H., and Miller, K. W. (eds.), Molecular and Cellular Mechanisms of Anesthetics, Plenum Medical Book, New York, pp. 243–260.

    Google Scholar 

  • Yarov-Yarovoy, V., Brown, J., Sharp, E., Clare, J. J., Scheuer, T., and Catterall, W. A. (2001). Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel α subunit. J. Biol. Chem. 276:20–27.

    Google Scholar 

  • Zamponi, G. W., Doyle, D. D., and French, R. J. (1993a). Fast lidocaine block of cardiac and skeletal muscle sodium channels: One site with two routes of access. Biophys. J. 65:80–90.

    Google Scholar 

  • Zamponi, G. W., Doyle, D. D., and French R. J. (1993b). State-dependent block underlies the tissue specificity of lidocaine action on batrachotoxin-activated cardiac sodium channels. Biophys. J. 65:91–100.

    Google Scholar 

  • Zamponi, G. W., and French, R. J. (1993). Dissecting lidocaine action: Diethylamide and phenol mimic separate modes of lidocaine block of sodium channels from heart and skeletal muscle. Biophys. J. 65:2324–2334.

    Google Scholar 

  • Zong, X. G., Dugas, M., and Honerjäger, P. (1992). Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells. J. Gen. Physiol. 99:683–697.

    Google Scholar 

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Authors and Affiliations

  1. Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts

    Stanley Lee Son, Kin Wong & Gary Strichartz

  2. Department of Biological and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts

    Gary Strichartz

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  1. Stanley Lee Son
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  2. Kin Wong
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Son, S.L., Wong, K. & Strichartz, G. Antagonism by Local Anesthetics of Sodium Channel Activators in the Presence of Scorpion Toxins: Two Mechanisms for Competitive Inhibition. Cell Mol Neurobiol 24, 565–577 (2004). https://doi.org/10.1023/B:CEMN.0000023630.16308.54

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  • DOI: https://doi.org/10.1023/B:CEMN.0000023630.16308.54

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