Abstract
A voltage clamp technique was used to study sodium currents and gating currents in squid axons internally perfused with the membrane impermeant sodium channel blocker, QX-314. Block by QX-314 is strongly and reversibly enhanced if a train of depolarizing pulses precedes the measurement. The depolarization-induced block is antagonized by external sodium. This antagonism provides evidence that the blocking site for the drug lies inside the channel. Depolarization-induced block of sodium current by QX-314 is accompanied by nearly twofold reduction in gating charge movement. This reduction does not add to a depolarization-induced immobilization of gating charge normally present and believed to be associated with inactivation of sodium channels. Failure to act additively suggests that both, inactivation and QX-314, affect the same component of gating charge movement. Judged from gating current measurement, a drug-blocked channel is an inactivated channel. In the presence of external tetrodotoxin and internal QX-314, gating charge movement is always half its normal size regardless of conditioning, as it QX-314 is then permanently present in the channel.
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Selected References
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- Adrian R. H., Almers W. Charge movement in the membrane of striated muscle. J Physiol. 1976 Jan;254(2):339–360. doi: 10.1113/jphysiol.1976.sp011235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Almers W. Differential effects of tetracaine on delayed potassium channels and displacement currents in frog skeletal muscle. J Physiol. 1976 Nov;262(3):613–637. doi: 10.1113/jphysiol.1976.sp011612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Almers W. Gating currents and charge movements in excitable membranes. Rev Physiol Biochem Pharmacol. 1978;82:96–190. doi: 10.1007/BFb0030498. [DOI] [PubMed] [Google Scholar]
- Almers W., Levinson S. R. Tetrodotoxin binding to normal depolarized frog muscle and the conductance of a single sodium channel. J Physiol. 1975 May;247(2):483–509. doi: 10.1113/jphysiol.1975.sp010943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armstrong C. M., Bezanilla F. Charge movement associated with the opening and closing of the activation gates of the Na channels. J Gen Physiol. 1974 May;63(5):533–552. doi: 10.1085/jgp.63.5.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armstrong C. M., Bezanilla F. Inactivation of the sodium channel. II. Gating current experiments. J Gen Physiol. 1977 Nov;70(5):567–590. doi: 10.1085/jgp.70.5.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armstrong C. M., Bezanilla F., Rojas E. Destruction of sodium conductance inactivation in squid axons perfused with pronase. J Gen Physiol. 1973 Oct;62(4):375–391. doi: 10.1085/jgp.62.4.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armstrong C. M. Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol. 1971 Oct;58(4):413–437. doi: 10.1085/jgp.58.4.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Begenisich T., Lynch C. Effects of internal divalent cations on voltage-clamped squid axons. J Gen Physiol. 1974 Jun;63(6):675–689. doi: 10.1085/jgp.63.6.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bezanilla F., Armstrong C. M. Inactivation of the sodium channel. I. Sodium current experiments. J Gen Physiol. 1977 Nov;70(5):549–566. doi: 10.1085/jgp.70.5.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cahalan M. D. Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons. Biophys J. 1978 Aug;23(2):285–311. doi: 10.1016/S0006-3495(78)85449-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cahalan M., Begenisich T. Sodium channel selectivity. Dependence on internal permeant ion concentration. J Gen Physiol. 1976 Aug;68(2):111–125. doi: 10.1085/jgp.68.2.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Colquhoun D., Henderson R., Ritchie J. M. The binding of labelled tetrodotoxin to non-myelinated nerve fibres. J Physiol. 1972 Dec;227(1):95–126. doi: 10.1113/jphysiol.1972.sp010022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Courtney K. R. Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther. 1975 Nov;195(2):225–236. [PubMed] [Google Scholar]
- Eaton D. C., Brodwick M. S., Oxford G. S., Rudy B. Arginine-specific reagents remove sodium channel inactivation. Nature. 1978 Feb 2;271(5644):473–476. doi: 10.1038/271473a0. [DOI] [PubMed] [Google Scholar]
- Frazier D. T., Narahashi T., Yamada M. The site of action and active form of local anesthetics. II. Experiments with quaternary compounds. J Pharmacol Exp Ther. 1970 Jan;171(1):45–51. [PubMed] [Google Scholar]
- HODGKIN A. L., HUXLEY A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952 Aug;117(4):500–544. doi: 10.1113/jphysiol.1952.sp004764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- HODGKIN A. L., HUXLEY A. F. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol. 1952 Apr;116(4):449–472. doi: 10.1113/jphysiol.1952.sp004717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hille B. Ionic selectivity, saturation, and block in sodium channels. A four-barrier model. J Gen Physiol. 1975 Nov;66(5):535–560. doi: 10.1085/jgp.66.5.535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. doi: 10.1085/jgp.69.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hille B., Schwarz W. Potassium channels as multi-ion single-file pores. J Gen Physiol. 1978 Oct;72(4):409–442. doi: 10.1085/jgp.72.4.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keynes R. D., Rojas E. Kinetics and steady-state properties of the charged system controlling sodium conductance in the squid giant axon. J Physiol. 1974 Jun;239(2):393–434. doi: 10.1113/jphysiol.1974.sp010575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meves H. The effect of holding potential on the asymmetry currents in squid gaint axons. J Physiol. 1974 Dec;243(3):847–867. doi: 10.1113/jphysiol.1974.sp010780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nonner W., Rojas E., Stämpfli R. Gating currents in the node of Ranvier: voltage and time dependence. Philos Trans R Soc Lond B Biol Sci. 1975 Jun 10;270(908):483–492. doi: 10.1098/rstb.1975.0024. [DOI] [PubMed] [Google Scholar]
- Ritchie J. M., Rogart R. B., Strichartz G. R. A new method for labelling saxitoxin and its binding to non-myelinated fibres of the rabbit vagus, lobster walking leg, and garfish olfactory nerves. J Physiol. 1976 Oct;261(2):477–494. doi: 10.1113/jphysiol.1976.sp011569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rojas E., Rudy B. Destruction of the sodium conductance inactivation by a specific protease in perfused nerve fibres from Loligo. J Physiol. 1976 Nov;262(2):501–531. doi: 10.1113/jphysiol.1976.sp011608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwarz W., Palade P. T., Hille B. Local anesthetics. Effect of pH on use-dependent block of sodium channels in frog muscle. Biophys J. 1977 Dec;20(3):343–368. doi: 10.1016/S0006-3495(77)85554-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shapiro B. I. Effects of strychnine on the sodium conductance of the frog node of Ranvier. J Gen Physiol. 1977 Jun;69(6):915–926. doi: 10.1085/jgp.69.6.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strichartz G. R. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol. 1973 Jul;62(1):37–57. doi: 10.1085/jgp.62.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Woodhull A. M. Ionic blockage of sodium channels in nerve. J Gen Physiol. 1973 Jun;61(6):687–708. doi: 10.1085/jgp.61.6.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yeh J. Z., Narahashi T. Kinetic analysis of pancuronium interaction with sodium channels in squid axon membranes. J Gen Physiol. 1977 Mar;69(3):293–323. doi: 10.1085/jgp.69.3.293. [DOI] [PMC free article] [PubMed] [Google Scholar]