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. 1983 Jun;80(12):3855–3859. doi: 10.1073/pnas.80.12.3855

Phencyclidine in nanomolar concentrations binds to synaptosomes and blocks certain potassium channels.

M P Blaustein, R K Ickowicz
PMCID: PMC394151  PMID: 6304743

Abstract

Phencyclidine [1-(phenylcyclohexyl)piperidine; PCP], in low dose (approximately equal to 0.1-0.2 mg/kg of body weight), induces a schizophrenia-like behavioral syndrome in man; this effect has been attributed to block of neuronal K channels. We used a K-stimulated 86Rb efflux assay to demonstrate that low concentrations of PCP (10-50 nM) block a class of depolarization-activated K channels in rat brain synaptosomes--pinched-off presynaptic nerve terminals. The dose-response curve is biphasic, and much higher PCP concentrations (greater than 10 microM) are required to block the remainder of the K-stimulated 86Rb efflux. The [3H]PCP binding curve for synaptosomes is also biphasic: PCP binds to some components with high affinity (Kd approximately equal to 6.0 X 10(-8) M), and to other components with much lower affinity (Kd approximately equal to 1.15 X 10(4) M). PCP can be photoactivated with UV light to form covalent bonds: after UV irradiation, previously-bound [3H]PCP is no longer displaceable by a large excess of unlabeled PCP. Preliminary data from NaDodSO4/polyacrylamide gel electrophoresis studies after covalent binding of [3H]PCP to synaptosomes, suggest that the high-affinity binding site may be on a large protein (Mr approximately equal to 220,000). We conclude that the high-affinity PCP binding protein is associated with the K channels that are blocked by nanomolar concentrations of PCP. Block of these channels could, by prolonging action-potential duration in presynaptic nerve terminals, enhance calcium entry and neurotransmitter release, thereby altering transmission at central synapses involved in behavioral expression.

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Selected References

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

  1. Aguayo L. G., Warnick J. E., Maayani S., Glick S. D., Weinstein H., Albuquerque E. X. Site of action of phencyclidine. IV. Interaction of phencyclidine and its analogues on ionic channels of the electrically excitable membrane and nicotinic receptor: implications for behavioral effects. Mol Pharmacol. 1982 May;21(3):637–647. [PubMed] [Google Scholar]
  2. Albuquerque E. X., Aguayo L. G., Warnick J. E., Weinstein H., Glick S. D., Maayani S., Ickowicz R. K., Blaustein M. P. The behavioral effects of phencyclidines may be due to their blockade of potassium channels. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7792–7796. doi: 10.1073/pnas.78.12.7792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Albuquerque E. X., Tsai M. C., Aronstam R. S., Witkop B., Eldefrawi A. T., Eldefrawi M. E. Phencyclidine interactions with the ionic channel of the acetylcholine receptor and electrogenic membrane. Proc Natl Acad Sci U S A. 1980 Feb;77(2):1224–1228. doi: 10.1073/pnas.77.2.1224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Armstrong C. M., Hille B. The inner quaternary ammonium ion receptor in potassium channels of the node of Ranvier. J Gen Physiol. 1972 Apr;59(4):388–400. doi: 10.1085/jgp.59.4.388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beneski D. A., Catterall W. A. Covalent labeling of protein components of the sodium channel with a photoactivable derivative of scorpion toxin. Proc Natl Acad Sci U S A. 1980 Jan;77(1):639–643. doi: 10.1073/pnas.77.1.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blaustein M. P. Effects of potassium, veratridine, and scorpion venom on calcium accumulation and transmitter release by nerve terminals in vitro. J Physiol. 1975 Jun;247(3):617–655. doi: 10.1113/jphysiol.1975.sp010950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gorman A. L., Woolum J. C., Cornwall M. C. Selectivity of the Ca2+-activated and light-dependent K+ channels for monovalent cations. Biophys J. 1982 Jun;38(3):319–322. doi: 10.1016/S0006-3495(82)84565-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hartshorne R. P., Catterall W. A. Purification of the saxitoxin receptor of the sodium channel from rat brain. Proc Natl Acad Sci U S A. 1981 Jul;78(7):4620–4624. doi: 10.1073/pnas.78.7.4620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Johnson K. M., Oeffinger K. C. The effect of phencyclidine on dopamine metabolism in the mouse brain. Life Sci. 1981 Jan 26;28(4):361–369. doi: 10.1016/0024-3205(81)90080-1. [DOI] [PubMed] [Google Scholar]
  10. Kloog Y., Kalir A., Buchman O., Sokolovsky M. Specific binding of [3H]phencyclidines to membrane preparation. Possible interaction with the cholinergic ionophore. FEBS Lett. 1980 Jan 1;109(1):125–128. doi: 10.1016/0014-5793(80)81325-1. [DOI] [PubMed] [Google Scholar]
  11. Krueger B. K., Ratzlaff R. W., Strichartz G. R., Blaustein M. P. Saxitoxin binding to synaptosomes, membranes, and solubilized binding sites from rat brain. J Membr Biol. 1979 Nov 30;50(3-4):287–310. doi: 10.1007/BF01868894. [DOI] [PubMed] [Google Scholar]
  12. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  13. Oswald R., Changeux J. P. Ultraviolet light-induced labeling by noncompetitive blockers of the acetylcholine receptor from Torpedo marmorata. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3925–3929. doi: 10.1073/pnas.78.6.3925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Quirion R., Pert C. B. Certain calcium antagonists are potent displacers of [3H]phencyclidine (PCP) binding in rat brain. Eur J Pharmacol. 1982 Sep 10;83(1-2):155–156. doi: 10.1016/0014-2999(82)90305-3. [DOI] [PubMed] [Google Scholar]
  15. Rappolt R. T., Sr, Gay G. R., Farris R. D. Phencyclidine (PCP) intoxication: diagnosis in stages and algorithms of treatment. Clin Toxicol. 1980 Jun;16(4):509–529. doi: 10.3109/15563658008989980. [DOI] [PubMed] [Google Scholar]
  16. Snyder S. H. Dopamine receptors, neuroleptics, and schizophrenia. Am J Psychiatry. 1981 Apr;138(4):460–464. doi: 10.1176/ajp.138.4.460. [DOI] [PubMed] [Google Scholar]
  17. Taube H. D., Montel H., Hau G., Starke K. Phencyclidine and ketamine: comparison with the effect of cocaine on the noradrenergic neurones of the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol. 1975;291(1):47–54. doi: 10.1007/BF00510820. [DOI] [PubMed] [Google Scholar]
  18. Tourneur Y., Romey G., Lazdunski M. Phencyclidine blockade of sodium and potassium channels in neuroblastoma cells. Brain Res. 1982 Aug 5;245(1):154–158. doi: 10.1016/0006-8993(82)90351-1. [DOI] [PubMed] [Google Scholar]
  19. Vincent J. P., Vignon J., Kartalovski B., Lazdunski M. Binding of phencyclidine to rat brain membranes: technical aspect. Eur J Pharmacol. 1980 Nov 7;68(1):73–77. doi: 10.1016/0014-2999(80)90064-3. [DOI] [PubMed] [Google Scholar]
  20. Zukin S. R., Zukin R. S. Specific [3H]phencyclidine binding in rat central nervous system. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5372–5376. doi: 10.1073/pnas.76.10.5372. [DOI] [PMC free article] [PubMed] [Google Scholar]

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