Abstract
Phencyclidine (PCP) binds with high affinity to the ion channel associated with the NMDA receptor. The binding of the PCP receptor-specific ligand TCP is greatly reduced at temperatures between 2°C and 6°C, at which the plasma membrane is in a rigid state. However, membrane rigidity alone does not appear to cause the reduced TCP binding, since the membrane fluidizing agent A2C did not increase TCP binding at 4°C; instead, it decreased binding at 21°C. This inhibitory effect of A2C on TCP binding was dose dependent and was highly correlated with A2C-induced increases in membrane fluidity. The IC50 of A2C inhibition was 8.9 mM, with a pseudo-Hill coefficient of −0.24. Scatchard analysis demonstrated that this effect was the result of an increase in the apparentK d of [3H]TCP for the PCP receptor, with no effect on theB max. These results suggest that the function of the NMDA-PCP receptor complex is impaired by increases in membrane fluidity. These findings may be pharmacologically relevant in understanding the mechanism of action of such agents as general anesthetics and ethanol, which cause increases in plasma membrane fluidity.
Similar content being viewed by others
References
Aniline, O., Pitts, F.N. (1982). Phencyclidine (PCP): A review and perspectives. CRC Crit. Rev. Toxicol. 10:145–177
Anis, N.A., Berry, S.C., Burton, N.R., Lodge, D. (1983). The dissociative anesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones byN-methyl-aspartate. Br. J. Pharmacol. 79: 565–575
Ascher, P., Nowak, L. (1986). Calcium permeability of the channels activated byN-methyl-d-aspartate in isolated mouse central neurones. J. Physiol. (London) 377:35P
Bartschat, D.K., Blaustein, M.P. (1988). Psychotomimetic sigma-ligands, dexoxadrol and phencyclidine block the same presynaptic potassium channel in rat brain. J. Physiol. (London) 403: 341–353
Byrd, J.C., Bykov, V., Rothman, R.B. (1987). Chronic haloperidol treatment up-regulates PCP receptors in rat brain. Eur. J. Pharmacol. 140: 121–122
Choi, D.W. (1988). Glutamate toxicity and diseases of the central nervous system. Neuron 1: 623–634
Clouet, D.H. (1986). Phencyclidine: An update. NIDA Res. Monogr. 64: 266 pp
Collingridge, G.L., Kehl, S.J., McLennan, H. (1983). Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J. Physiol. (London) 334: 33–46
Cotman, C.W., Iversen, L.L. (eds). Excitatory amino acids in the brain—focus on NMDA receptors. Trends Neurosci. 10(7): 263–265
DePietro, F., Byrd, J.C. (1990). Effects of membrane fluidity on [3H]TCP binding. FASEB J 4(3): A602
Domino, E.P., Kamenka, J.M. (1988). Sigma and Phencyclidine-like Compounds as Molecular Probes NPP Books, Ann Arbor, MI
Duchen, M.R., Burton, N.R., Biscoe, T.J. (1985). An intracellular study of the interactions ofN-methyl-d-aspartate with ketamine in the mouse hippocampal slice. Brain Res. 342: 149–153
Engberg, I., Flatman, J.A., Lambert, J.D.C. (1979). The actions of excitatory amino acids on motoneurons in the feline spinal cord. J. Physiol. 288: 227–260
Flatman, J.A., Schwindt, P.C., Crill, W.E., Stafstrom, C.E. (1983) Multiple actions ofN-methyl-d-aspartate on cat neocortical neurons in vitro. Brain Res. 266: 169–173
Foster, A.C., Fagg, G.E. (1984). Acidic amino acid binding sites in mammalian neuronal membranes: Their characteristics and relationship to synaptic receptors. Brain Res. Rev. 7: 103–164
Furchgott, R.F. (1955). The pharmacology of vascular smooth muscle. Pharmacol. Rev. 7: 183–265
Gundlach, A.L., Largent, B.L., Snyder, S.H. (1985). Phencyclidine and Sigma opiate receptors in brain: Biochemical and autoradiographic differentiation. Eur. J. Pharmacol. 113: 465–466
Gundlach, A.L., Largent, B.L., Snyder, S.H. (1986). Autoradiographic localization of Sigma receptor binding sites in guinea pig and rat central nervous system with (+)[3H]-3(3-hydroxyphenyl)-N-(1-propyl)piperidine. J. Neurosci. 6: 1757–1770
Harrison, N.L., Simmonds, M.A. (1985). Quantitative studies on some antagonists ofN-methyl-d-aspartate in slices of rat cerebral cortex. Br. J. Pharmacol. 84: 381–391
Hoffman, P.L., Rabe, C.S., Moses, F., Tabakoff, B. (1989).N-Methyl-d-aspartate receptors and ethanol: Inhibition of calcium flux and cyclic GMP production. J. Neurochem. 52: 1937–1940
Honey, C.R., Miljkovic, Z., MacDonald, J.F. (1985). Ketamine and phencyclidine cause a voltage-dependent block of responses tol-aspartic acid. Neurosci. Lett. 61: 135–139
Hunt, W.A. (1985). Alcohol and Biological Membranes. Guilford Press, New York, 214 pp
Johnson, J.W., Ascher, P. (1987). Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325: 529–531
Kleinschmidt, A., Bear, M.F., Singer, W. (1987). Blockade of “NMDA” receptors disrupts experience-dependent plasticity of kitten striate cortex. Science 238: 355–358
Kloog, Y., Haring, R., Sokolovsky, M. (1988). Kinetic characterization of the phencyclidine-N-methyl-d-aspartate receptor interaction: Evidence for a steric blockade of the channel. Biochemistry 27: 843–848
Kosower, E.M., Kosower, N.S., Faltin, Z., Diver, A., Saltoun, G., Frensdorff, A. (1974). Membrane mobility agents: A new class of biologically active molecules. Biochim. Biophys. Acta 363: 261–266
Largent, B.L., Gundlach, A.L., Snyder, S.H. (1986). Pharmacological and autoradiographic discrimination of Sigma and phencyclidine receptor binding sites in brain with (+)[3H]SKF 10,047, (+)[3H]3-PPP and [3H]TCP. J. Pharmacol. Exp. Ther. 238: 739–745
Lakowicz, J.R.,(1983). Principles of Fluorescence Spectroscopy. Plenum Press, New York
Lakowicz, J.R., Prendergast, F.G. (1978). Quantitation of hindered rotations of diphenylhexatriene in lipid bilayers by differential polarized phase fluorometry. Science 200: 1399–1407
Lakowicz, J.R., Prendergast, F.G., Hogen, D. (1979). Differential polarized phase fluorometric investigations of diphenylhexatriene in lipid bilayers: Quantitation of hindered depolarizing rotations. Biochemistry 18: 508–519
Lima-Landmand, M.R., Albuquerque, E.X. (1989). Ethanol potentiates and blocks NMDA-activated single-channel currents in rat hippocampal pyramidal cells. FEBS Lett. 247: 61–67
Lincoln, J., Coopersmith, R., Harris, E.W., Cotman, C.W., Leon, M. (1988). NMDA receptor activation and early olfactory learning. Dev. Brain Res. 39: 309–312
Loo, P., Braunwalder, A., Lehmann, J., Williams, M. (1986). Radioligand binding to central phencyclidine recognition sites is dependent on excitatory amino acid receptor agonists. Eur. J. Pharmacol. 123: 467–468
Loo, P.S., Braunwalder, A.F., Lehmann, J., Williams, M., Sills, M.A. (1988). Interaction ofl-glutamate and magnesium with phencyclidine recognition sites in rat brain: Evidence for multiple affinity states of the phencyclidine/N-methyl-d-aspartate receptor complex. Mol. Pharmacol. 32: 820–830
Lovinger, D.M., White, G., Weight, F.F. (1989). Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724
MacDermott, A.B., Mayer, M.L., Westbrook, G.L., Smith, S.J., Barker, J.L. (1986). NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature (London) 321:519–522
MacDonald, J.F., Porietis, A.V., Wojtowicz, J.M. (1982).l-Aspartic acid induces a region of negative slope conductance in the current-voltage relationship of cultured spinal cord neurons. Brain Res. 237:248–253
Maragos, W.F., Chu, D.C.M., Greenamyre, J.T., Penney, J.B., Young, A.B. (1986). High correlation between the localization of [3H]TCP binding and NMDA receptors. Eur. J. Pharmacol. 123:173–174
Maragos, W.F., Penney, J.B., Young, A.B. (1988). Anatomic correlation of NMDA and [3H]TCP-labeled receptors in rat brain. J. Neurosci. 8(2):493–501
Martin, D., Lodge, D. (1985). Ketamine acts as a noncompetitiveN-methyl-d-aspartate antagonist on frog spinal cord in vitro. Neuropharmacology 24:999–1003
Mayer, M.L., Westbrook, G.L. (1987). The physiology of excitatory amino acids in the vertebrate nervous system. Prog. Neurobiol. (Oxford) 28:197–276
Munson, P.J., Rodbard, D. (1980). LIGAND: A versatile computerized approach for characterization of ligand-binding systems. Anal. Biochem. 107:220–239
Murphy, S.N., Thayer, S.A., Miller, R.J. (1987). The effects of excitatory amino acids on intracellular calcium in single mouse striatal neurons in vitro. J. Neurosci. 7:4145–4158
Olney, J.W. (1989). Excitatory amino acid and neuropsychiatric disorders. Biol. Psychiatry 26:505–525
Paleos, G.A., Yang, Z.W., Byrd, J.C. (1990). Ontogeny of PCP and Sigma receptors in rat brain. Dev. Brain Res. 51(2):147–152
Reynolds, I.J., Miller, R.J. (1988). Multiple sites for the regulation of theN-methyl-d-aspartate receptor. Mol. Pharmacol. 33:581–584
Reynolds, I.J., Murphy, S.N., Miller, R.J. (1987).3H-labeled MK-801 binding to the excitatory amino acid receptor complex from rat brain is enhanced by glycine. Proc. Natl. Acad. Sci. U.S.A. 84:7744–7748
Siebke, H., Breivik, H., Rod, T., Lind, B. (1975). Survival after 40 minutes' submersion without cerebral sequelae. Lancet 1:1275–1277
Snell, L.D., Morter, R.S., Johnson, K.M. (1987). Glycine potentiatesN-methyl-d-aspartate-induced [3H]TCP binding to rat cortical membranes. Neurosci. Lett. 83:313–317
Sonders, M.S., Keana, J.F.W., Weber, E. (1988). Phencyclidine and psychotomimetic opiates: Recent insights into their biochemical and physiological sites of action. Trends Neurosci. 11(1):37–40
Vignon, J., Chicheportiche, R., Chicheportiche, M., Kamenka, J.M., Geneste, P., Lazdunski, M. (1983). [3H]TCP: A new tool with high affinity for the PCP receptor in rat brain. Brain Res. 280:194–197
Vincent, J.P., Vignon, J., Kartalovski, B., Geneste, P., Kamenka, J.M., Lazdunski, M. (1979). Interaction of phencyclidine (“angel dust”) with a specific receptor in rat brain membranes. Proc. Natl. Acad. Sci. U.S.A. 76:4678–4682
Weissmann, G., Claiborne, R. (1975). Cell Membranes: Biochemistry, Cell Biology, and Pathology. H.P. Publishing Company, New York
Wong, E.H.F., Knight, A.R., Ransom, R. (1987). Glycine modulates [3H]MK-801 binding to the NMDA receptor in rat brain. Eur. J. Pharmacol. 142:487–488
Wroblewski, J.T., Nicoletti, F., Fadda, E., Costa, E. (1987). Phencyclidine is a negative allosteric modulator of signal transduction at two subclasses of excitatory amino acid receptors. Proc. Natl. Acad. Sci. U.S.A. 84:5068–5072
Yang, Z.W., Paleos, G.A., Byrd, J.C. (1988). PCP and Sigma receptors: Differential effects of cations and pH on ligand affinity. Soc. Neurosci. Abst. 14(1):485
Zubenko, G. (1986). Hippocampal membrane alteration in Alzheimer's disease. Brain Res. 385:115–121
Zubenko, G., Cohen, B.M. (1985). Effects of phenothiazine treatment on the physical properties of platelet membranes from psychiatric patients. Biol. Psychiatry 20:384–396
Zukin, S.R., Zukin, R.S. (1979). Specific [3H]phencyclidine binding in rat central nervous system. Proc. Natl. Acad. Sci. U.S.A. 76:5372–5376
Author information
Authors and Affiliations
Additional information
Frank DePietro is the recipient of an NIH Medical Scientist Training Award to the University of Pittsburgh College of Medicine. This research was supported in part by NIMH grant MH30915.
Rights and permissions
About this article
Cite this article
DePietro, F.R., Byrd, J.C. Effects of membrane fluidity on [3H]TCP binding to PCP receptors. J Mol Neurosci 2, 45–52 (1990). https://doi.org/10.1007/BF02896925
Issue Date:
DOI: https://doi.org/10.1007/BF02896925