Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1994 Mar;111(3):663–672. doi: 10.1111/j.1476-5381.1994.tb14789.x

Local anaesthetic blockade of neuronal nicotinic ACh receptor-channels in rat parasympathetic ganglion cells.

J Cuevas 1, D J Adams 1
PMCID: PMC1910063  PMID: 7517326

Abstract

1 The effects of the local anaesthetics QX-222 and procaine on nicotinic acetylcholine (ACh)-evoked currents in cultured parasympathetic cardiac neurones of the rat were investigated by use of the whole-cell, perforated-patch, and outside-out recording configurations of the patch clamp method. 2 QX-222 and procaine, applied to the extracellular surface, reversibly inhibited the peak amplitude of the whole-cell nicotinic ACh-evoked current in a concentration-dependent manner, with half-maximal inhibitory concentrations (IC50) of 28 microM and 2.8 microM, respectively, at -80 mV. In these neurones, the sustained inward current mediated by M1 muscarinic receptor activation was unaltered by QX-222, and neither local anaesthetic affected the adenosine 5'-triphosphate (ATP)-evoked current. 3 QX-222 and procaine block of nicotinic ACh-evoked inward current was voltage-dependent and enhanced by hyperpolarization. An e-fold change in their dissociation equilibrium constants (Kd) resulted from a 62 mV and a 122 mV change in membrane potential, respectively. 4 Both local anaesthetics produce a concentration-dependent increase in the half-time of decay of the nicotinic ACh-evoked inward current. 5 Measurements of unitary currents in outside-out patches showed that QX-222 reversibly increased the mean burst duration and closed time and reduced the mean channel open time and open-state probability of the nicotinic ACh receptor-channel (AChR) in a concentration-dependent manner. 6 The Kd and voltage sensitivity of local anaesthetic block of the nicotinic AChR in rat intracardiac neurones suggests that the pore-forming region of this channel differs from that of the AChR in frog and rat skeletal muscle and from the neuronal alpha 4 beta 2 ACh receptor-channel.

Full text

PDF
663

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams D. J., Nutter T. J. Calcium permeability and modulation of nicotinic acetylcholine receptor-channels in rat parasympathetic neurons. J Physiol Paris. 1992;86(1-3):67–76. doi: 10.1016/s0928-4257(05)80009-9. [DOI] [PubMed] [Google Scholar]
  2. Adams P. R. Drug blockade of open end-plate channels. J Physiol. 1976 Sep;260(3):531–552. doi: 10.1113/jphysiol.1976.sp011530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Adams P. R. Voltage jump analysis of procaine action at frog end-plate. J Physiol. 1977 Jun;268(2):291–318. doi: 10.1113/jphysiol.1977.sp011858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Alary J. G., Brodeur J. Studies on the mechanism of phenobarbital-induced protection against parathion in adult female rats. J Pharmacol Exp Ther. 1969 Oct;169(2):159–167. [PubMed] [Google Scholar]
  5. Allen T. G., Burnstock G. M1 and M2 muscarinic receptors mediate excitation and inhibition of guinea-pig intracardiac neurones in culture. J Physiol. 1990 Mar;422:463–480. doi: 10.1113/jphysiol.1990.sp017995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Allen T. G., Burnstock G. The actions of adenosine 5'-triphosphate on guinea-pig intracardiac neurones in culture. Br J Pharmacol. 1990 Jun;100(2):269–276. doi: 10.1111/j.1476-5381.1990.tb15794.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Anand R., Conroy W. G., Schoepfer R., Whiting P., Lindstrom J. Neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes have a pentameric quaternary structure. J Biol Chem. 1991 Jun 15;266(17):11192–11198. [PubMed] [Google Scholar]
  8. Ascher P., Large W. A., Rang H. P. Studies on the mechanism of action of acetylcholine antagonists on rat parasympathetic ganglion cells. J Physiol. 1979 Oct;295:139–170. doi: 10.1113/jphysiol.1979.sp012958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Beam K. G. A quantitative description of end-plate currents in the presence of two lidocaine derivatives. J Physiol. 1976 Jun;258(2):301–322. doi: 10.1113/jphysiol.1976.sp011421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Beam K. G. A voltage-clamp study of the effect of two lidocaine derivatives on the time course of end-plate currents. J Physiol. 1976 Jun;258(2):279–300. doi: 10.1113/jphysiol.1976.sp011420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Charlesworth P., Jacobson I., Pocock G., Richards C. D. The mechanism by which procaine inhibits catecholamine secretion from bovine chromaffin cells. Br J Pharmacol. 1992 Aug;106(4):802–812. doi: 10.1111/j.1476-5381.1992.tb14416.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Charnet P., Labarca C., Cohen B. N., Davidson N., Lester H. A., Pilar G. Pharmacological and kinetic properties of alpha 4 beta 2 neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Physiol. 1992 May;450:375–394. doi: 10.1113/jphysiol.1992.sp019132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Charnet P., Labarca C., Leonard R. J., Vogelaar N. J., Czyzyk L., Gouin A., Davidson N., Lester H. A. An open-channel blocker interacts with adjacent turns of alpha-helices in the nicotinic acetylcholine receptor. Neuron. 1990 Jan;4(1):87–95. doi: 10.1016/0896-6273(90)90445-l. [DOI] [PubMed] [Google Scholar]
  14. Clapham D. E., Neher E. Substance P reduces acetylcholine-induced currents in isolated bovine chromaffin cells. J Physiol. 1984 Feb;347:255–277. doi: 10.1113/jphysiol.1984.sp015065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Colquhoun D., Sakmann B. Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate. J Physiol. 1985 Dec;369:501–557. doi: 10.1113/jphysiol.1985.sp015912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cooper E., Couturier S., Ballivet M. Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor. Nature. 1991 Mar 21;350(6315):235–238. doi: 10.1038/350235a0. [DOI] [PubMed] [Google Scholar]
  17. Dani J. A. Site-directed mutagenesis and single-channel currents define the ionic channel of the nicotinic acetylcholine receptor. Trends Neurosci. 1989 Apr;12(4):125–128. doi: 10.1016/0166-2236(89)90049-0. [DOI] [PubMed] [Google Scholar]
  18. Deneris E. S., Connolly J., Rogers S. W., Duvoisin R. Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors. Trends Pharmacol Sci. 1991 Jan;12(1):34–40. doi: 10.1016/0165-6147(91)90486-c. [DOI] [PubMed] [Google Scholar]
  19. Fieber L. A., Adams D. J. Acetylcholine-evoked currents in cultured neurones dissociated from rat parasympathetic cardiac ganglia. J Physiol. 1991 Mar;434:215–237. doi: 10.1113/jphysiol.1991.sp018466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fieber L. A., Adams D. J. Adenosine triphosphate-evoked currents in cultured neurones dissociated from rat parasympathetic cardiac ganglia. J Physiol. 1991 Mar;434:239–256. doi: 10.1113/jphysiol.1991.sp018467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gage P. W., Hamill O. P., Wachtel R. E. Sites of action of procaine at the motor end-plate. J Physiol. 1983 Feb;335:123–137. doi: 10.1113/jphysiol.1983.sp014524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  23. Hassall C. J., Buckley N. J., Burnstock G. Autoradiographic localisation of muscarinic receptors on guinea pig intracardiac neurones and atrial myocytes in culture. Neurosci Lett. 1987 Feb 24;74(2):145–150. doi: 10.1016/0304-3940(87)90140-6. [DOI] [PubMed] [Google Scholar]
  24. Horn R., Brodwick M. S., Dickey W. D. Asymmetry of the acetylcholine channel revealed by quaternary anesthetics. Science. 1980 Oct 10;210(4466):205–207. doi: 10.1126/science.6251552. [DOI] [PubMed] [Google Scholar]
  25. Horn R., Marty A. Muscarinic activation of ionic currents measured by a new whole-cell recording method. J Gen Physiol. 1988 Aug;92(2):145–159. doi: 10.1085/jgp.92.2.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. LARRABEE M. G., POSTERNAK J. M. Selective action of anesthetics on synapses and axons in mammalian sympathetic ganglia. J Neurophysiol. 1952 Mar;15(2):91–114. doi: 10.1152/jn.1952.15.2.91. [DOI] [PubMed] [Google Scholar]
  27. Leonard R. J., Labarca C. G., Charnet P., Davidson N., Lester H. A. Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor. Science. 1988 Dec 16;242(4885):1578–1581. doi: 10.1126/science.2462281. [DOI] [PubMed] [Google Scholar]
  28. Luetje C. W., Patrick J. Both alpha- and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors. J Neurosci. 1991 Mar;11(3):837–845. doi: 10.1523/JNEUROSCI.11-03-00837.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Luetje C. W., Wada K., Rogers S., Abramson S. N., Tsuji K., Heinemann S., Patrick J. Neurotoxins distinguish between different neuronal nicotinic acetylcholine receptor subunit combinations. J Neurochem. 1990 Aug;55(2):632–640. doi: 10.1111/j.1471-4159.1990.tb04180.x. [DOI] [PubMed] [Google Scholar]
  30. Lukas R. J., Bencherif M. Heterogeneity and regulation of nicotinic acetylcholine receptors. Int Rev Neurobiol. 1992;34:25–131. doi: 10.1016/s0074-7742(08)60097-5. [DOI] [PubMed] [Google Scholar]
  31. Mathie A., Cull-Candy S. G., Colquhoun D. Conductance and kinetic properties of single nicotinic acetylcholine receptor channels in rat sympathetic neurones. J Physiol. 1991 Aug;439:717–750. doi: 10.1113/jphysiol.1991.sp018690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Neher E., Steinbach J. H. Local anaesthetics transiently block currents through single acetylcholine-receptor channels. J Physiol. 1978 Apr;277:153–176. doi: 10.1113/jphysiol.1978.sp012267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Neher E. The charge carried by single-channel currents of rat cultured muscle cells in the presence of local anaesthetics. J Physiol. 1983 Jun;339:663–678. doi: 10.1113/jphysiol.1983.sp014741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Papke R. L. The kinetic properties of neuronal nicotinic receptors: genetic basis of functional diversity. Prog Neurobiol. 1993 Oct;41(4):509–531. doi: 10.1016/0301-0082(93)90028-q. [DOI] [PubMed] [Google Scholar]
  35. Ruff R. L. A quantitative analysis of local anaesthetic alteration of miniature end-plate currents and end-plate current fluctuations. J Physiol. 1977 Jan;264(1):89–124. doi: 10.1113/jphysiol.1977.sp011659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ruff R. L. The kinetics of local anesthetic blockade of end-plate channels. Biophys J. 1982 Mar;37(3):625–631. [PMC free article] [PubMed] [Google Scholar]
  37. Sargent P. B. The diversity of neuronal nicotinic acetylcholine receptors. Annu Rev Neurosci. 1993;16:403–443. doi: 10.1146/annurev.ne.16.030193.002155. [DOI] [PubMed] [Google Scholar]
  38. Seabrook G. R., Fieber L. A., Adams D. J. Neurotransmission in neonatal rat cardiac ganglion in situ. Am J Physiol. 1990 Oct;259(4 Pt 2):H997–1005. doi: 10.1152/ajpheart.1990.259.4.H997. [DOI] [PubMed] [Google Scholar]
  39. Selyanko A. A., Skok V. I. Acetylcholine receptors in rat cardiac neurones. J Auton Nerv Syst. 1992 Aug;40(1):33–47. doi: 10.1016/0165-1838(92)90223-4. [DOI] [PubMed] [Google Scholar]
  40. Tabatabai M., Booth A. M. Mechanism of action of local anesthetics on synaptic transmission in the rat. Anesth Analg. 1990 Aug;71(2):149–157. doi: 10.1213/00000539-199008000-00007. [DOI] [PubMed] [Google Scholar]
  41. 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]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES