Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 1992 Oct;456:85–105. doi: 10.1113/jphysiol.1992.sp019328

Phencyclidine block of calcium current in isolated guinea-pig hippocampal neurones.

J M Ffrench-Mullen 1, M A Rogawski 1
PMCID: PMC1175673  PMID: 1338108

Abstract

1. Phencyclidine (PCP) block of Ca2+ channel current in enzymatically dissociated neurones from the CA1 region of the adult guinea-pig hippocampus was studied using whole-cell voltage clamp techniques. Ca2+ channel current was recorded with 3 mM-Ba2+ as the charge carrier. Na+ currents were blocked with tetrodotoxin and K+ currents were eliminated by using tetraethylammonium and N-methyl-D-glucamine as the predominant extracellular and intracellular cations, respectively. 2. Peak Ca2+ channel current evoked by depolarization from -80 to -10 mV was reduced in a use-dependent fashion by PCP. The apparent forward and reverse rate constants for block at the depolarized voltage were 10(6) s-1 M-1 and 11-14 s-1, respectively. These values were at least 60 times faster than the corresponding rates at the resting voltage. The steady-state block produced by PCP increased in a concentration-dependent fashion with an IC50 of 7 microM. Other dissociative anaesthetic drugs were substantially weaker inhibitors of the current (tiletamine > dizocilpine (MK-801) > ketamine). 3. The Ca2+ channel current recorded under identical conditions in rat dorsal root ganglion neurones was less sensitive to blockade by PCP (IC50, 90 microM). 4. PCP block of the hippocampal Ca2+ channel current occurred in a voltage-dependent fashion with the fractional block decreasing at positive membrane potentials. Analysis indicated that the PCP blocking site senses 56% of the transmembrane electric field. 5. Analysis of tail currents recorded at -80 mV demonstrated that PCP does not affect the voltage-dependent or time-dependent activation or deactivation of the Ca2+ channel current. 6. The rate and extent of inactivation of the Ca2+ channel current was maximal at -10 mV and diminished at more positive potentials. Experiments with Ba(2+)-free external solution demonstrated that inactivation of the Ca2+ channels is largely voltage-dependent and is not affected by Ba2+ influx. 7. PCP markedly increased the apparent extent of inactivation of the Ca2+ channel current during prolonged voltage steps. This increase in apparent inactivation was more pronounced at depolarized potentials. Inactivation at -10 mV proceeded in two exponential phases; PCP had little effect on the fast decay phase and caused a moderate speeding of the slow decay phase. Although block of the activated state evolved on the same time scale as inactivation, the apparent rate of inactivation was not increased in a concentration-dependent fashion by PCP indicating that the block does not occur by a conventional open channel mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

Full text

PDF
85

Selected References

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

  1. Aguayo L. G., Albuquerque E. X. Effects of phencyclidine and its analogs on the end-plate current of the neuromuscular junction. J Pharmacol Exp Ther. 1986 Oct;239(1):15–24. [PubMed] [Google Scholar]
  2. Aguayo L. G., Weinstein H., Maayani S., Glick S. D., Warnick J. E., Albuquerque E. X. Discriminant effects of behaviorally active and inactive analogs of phencyclidine on membrane electrical excitability. J Pharmacol Exp Ther. 1984 Jan;228(1):80–87. [PubMed] [Google Scholar]
  3. Bean B. P. Classes of calcium channels in vertebrate cells. Annu Rev Physiol. 1989;51:367–384. doi: 10.1146/annurev.ph.51.030189.002055. [DOI] [PubMed] [Google Scholar]
  4. Bean B. P., Cohen C. J., Tsien R. W. Lidocaine block of cardiac sodium channels. J Gen Physiol. 1983 May;81(5):613–642. doi: 10.1085/jgp.81.5.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Byerly L., Yazejian B. Intracellular factors for the maintenance of calcium currents in perfused neurones from the snail, Lymnaea stagnalis. J Physiol. 1986 Jan;370:631–650. doi: 10.1113/jphysiol.1986.sp015955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carbone E., Lux H. D. Single low-voltage-activated calcium channels in chick and rat sensory neurones. J Physiol. 1987 May;386:571–601. doi: 10.1113/jphysiol.1987.sp016552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Changeux J. P., Pinset C., Ribera A. B. Effects of chlorpromazine and phencyclidine on mouse C2 acetylcholine receptor kinetics. J Physiol. 1986 Sep;378:497–513. doi: 10.1113/jphysiol.1986.sp016232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coleman M. H., Yamaguchi S., Rogawski M. A. Protection against dendrotoxin-induced clonic seizures in mice by anticonvulsant drugs. Brain Res. 1992 Mar 13;575(1):138–142. doi: 10.1016/0006-8993(92)90433-a. [DOI] [PubMed] [Google Scholar]
  9. Collingridge G. L., Lester R. A. Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev. 1989 Jun;41(2):143–210. [PubMed] [Google Scholar]
  10. Doerner D., Alger B. E. Cyclic GMP depresses hippocampal Ca2+ current through a mechanism independent of cGMP-dependent protein kinase. Neuron. 1988 Oct;1(8):693–699. doi: 10.1016/0896-6273(88)90168-7. [DOI] [PubMed] [Google Scholar]
  11. Doerner D., Pitler T. A., Alger B. E. Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons. J Neurosci. 1988 Nov;8(11):4069–4078. doi: 10.1523/JNEUROSCI.08-11-04069.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dupont J. L., Bossu J. L., Feltz A. Effect of internal calcium concentration on calcium currents in rat sensory neurones. Pflugers Arch. 1986 Apr;406(4):433–435. doi: 10.1007/BF00590950. [DOI] [PubMed] [Google Scholar]
  13. Eckert R., Chad J. E. Inactivation of Ca channels. Prog Biophys Mol Biol. 1984;44(3):215–267. doi: 10.1016/0079-6107(84)90009-9. [DOI] [PubMed] [Google Scholar]
  14. FRANKENHAEUSER B., HODGKIN A. L. The action of calcium on the electrical properties of squid axons. J Physiol. 1957 Jul 11;137(2):218–244. doi: 10.1113/jphysiol.1957.sp005808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fisher R. E., Gray R., Johnston D. Properties and distribution of single voltage-gated calcium channels in adult hippocampal neurons. J Neurophysiol. 1990 Jul;64(1):91–104. doi: 10.1152/jn.1990.64.1.91. [DOI] [PubMed] [Google Scholar]
  16. Forscher P., Oxford G. S. Modulation of calcium channels by norepinephrine in internally dialyzed avian sensory neurons. J Gen Physiol. 1985 May;85(5):743–763. doi: 10.1085/jgp.85.5.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fox A. P., Nowycky M. C., Tsien R. W. Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones. J Physiol. 1987 Dec;394:149–172. doi: 10.1113/jphysiol.1987.sp016864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fox A. P., Nowycky M. C., Tsien R. W. Single-channel recordings of three types of calcium channels in chick sensory neurones. J Physiol. 1987 Dec;394:173–200. doi: 10.1113/jphysiol.1987.sp016865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hadley R. W., Hume J. R. Actions of phencyclidine on the action potential and membrane currents of single guinea-pig myocytes. J Pharmacol Exp Ther. 1986 Apr;237(1):131–136. [PubMed] [Google Scholar]
  20. Hille B., Woodhull A. M., Shapiro B. I. Negative surface charge near sodium channels of nerve: divalent ions, monovalent ions, and pH. Philos Trans R Soc Lond B Biol Sci. 1975 Jun 10;270(908):301–318. doi: 10.1098/rstb.1975.0011. [DOI] [PubMed] [Google Scholar]
  21. Hiramatsu M., Cho A. K., Nabeshima T. Comparison of the behavioral and biochemical effects of the NMDA receptor antagonists, MK-801 and phencyclidine. Eur J Pharmacol. 1989 Aug 3;166(3):359–366. doi: 10.1016/0014-2999(89)90346-4. [DOI] [PubMed] [Google Scholar]
  22. Jones S. W., Marks T. N. Calcium currents in bullfrog sympathetic neurons. II. Inactivation. J Gen Physiol. 1989 Jul;94(1):169–182. doi: 10.1085/jgp.94.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kay A. R. Inactivation kinetics of calcium current of acutely dissociated CA1 pyramidal cells of the mature guinea-pig hippocampus. J Physiol. 1991 Jun;437:27–48. doi: 10.1113/jphysiol.1991.sp018581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kay A. R., Wong R. K. Calcium current activation kinetics in isolated pyramidal neurones of the Ca1 region of the mature guinea-pig hippocampus. J Physiol. 1987 Nov;392:603–616. doi: 10.1113/jphysiol.1987.sp016799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kay A. R., Wong R. K. Isolation of neurons suitable for patch-clamping from adult mammalian central nervous systems. J Neurosci Methods. 1986 May;16(3):227–238. doi: 10.1016/0165-0270(86)90040-3. [DOI] [PubMed] [Google Scholar]
  26. Lacey M. G., Henderson G. Actions of phencyclidine on rat locus coeruleus neurones in vitro. Neuroscience. 1986 Feb;17(2):485–494. doi: 10.1016/0306-4522(86)90261-7. [DOI] [PubMed] [Google Scholar]
  27. Lehmann-Masten V. D., Geyer M. A. Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats. Neuropharmacology. 1991 Jun;30(6):629–636. doi: 10.1016/0028-3908(91)90083-n. [DOI] [PubMed] [Google Scholar]
  28. MacDonald J. F., Bartlett M. C., Mody I., Pahapill P., Reynolds J. N., Salter M. W., Schneiderman J. H., Pennefather P. S. Actions of ketamine, phencyclidine and MK-801 on NMDA receptor currents in cultured mouse hippocampal neurones. J Physiol. 1991 Jan;432:483–508. doi: 10.1113/jphysiol.1991.sp018396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. MacDonald J. F., Nowak L. M. Mechanisms of blockade of excitatory amino acid receptor channels. Trends Pharmacol Sci. 1990 Apr;11(4):167–172. doi: 10.1016/0165-6147(90)90070-O. [DOI] [PubMed] [Google Scholar]
  30. Papke R. L., Oswald R. E. Mechanisms of noncompetitive inhibition of acetylcholine-induced single-channel currents. J Gen Physiol. 1989 May;93(5):785–811. doi: 10.1085/jgp.93.5.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Plummer M. R., Logothetis D. E., Hess P. Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron. 1989 May;2(5):1453–1463. doi: 10.1016/0896-6273(89)90191-8. [DOI] [PubMed] [Google Scholar]
  32. Siegel R. K. Phencyclidine and ketamine intoxication: a study of four populations of recreational users. NIDA Res Monogr. 1978 Aug;(21):119–147. [PubMed] [Google Scholar]
  33. Slesinger P. A., Lansman J. B. Inactivation of calcium currents in granule cells cultured from mouse cerebellum. J Physiol. 1991 Apr;435:101–121. doi: 10.1113/jphysiol.1991.sp018500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Starmer C. F., Grant A. O. Phasic ion channel blockade. A kinetic model and parameter estimation procedure. Mol Pharmacol. 1985 Oct;28(4):348–356. [PubMed] [Google Scholar]
  35. Starmer C. F., Packer D. L., Grant A. O. Ligand binding to transiently accessible sites: mechanisms for varying apparent binding rates. J Theor Biol. 1987 Feb 7;124(3):335–341. doi: 10.1016/s0022-5193(87)80120-0. [DOI] [PubMed] [Google Scholar]
  36. Wada A., Arita M., Yanagihara N., Izumi F. Binding of [3H]phencyclidine to adrenal medullary cells: inhibition of 22Na influx, 45Ca influx, 86Rb efflux and catecholamine secretion caused by carbachol and veratridine. Neuroscience. 1988 May;25(2):687–696. doi: 10.1016/0306-4522(88)90269-2. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Yamaguchi S., Rogawski M. A. Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice. Epilepsy Res. 1992 Mar;11(1):9–16. doi: 10.1016/0920-1211(92)90016-m. [DOI] [PubMed] [Google Scholar]
  39. ffrench-Mullen J. M., Rogawski M. A. Interaction of phencyclidine with voltage-dependent potassium channels in cultured rat hippocampal neurons: comparison with block of the NMDA receptor-ionophore complex. J Neurosci. 1989 Nov;9(11):4051–4061. doi: 10.1523/JNEUROSCI.09-11-04051.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES