[3H]MK801 binding to the NMDA receptor/ionophore complex is regulated by divalent cations: evidence for multiple regulatory sites

https://doi.org/10.1016/0014-2999(88)90697-8Get rights and content

Abstract

We have examined the ability of divalent and trivalent cations to regulate [3H]MK801 binding to the N-methyl-D- aspartate operated ionophore of rat brain membranes. In EDTA-washed membranes that are nominally free of glutamate and glycine the cations Ba2+, Ca2+, Co2+, La3+, Mn2+,and Sr2+ increased [3H]MK801 binding in the range 0.01–10 mM, depending on the cation studied. At higher concentrations (0.1–30 mM) these cations all inhibited binding. In contrast, Cd2+, Hg2+, Mg2+, Ni2+ and Zn2+ inhibited binding at all concentrations tested. The addition of maximally effective concentrations of glutamate (100 μM) and glycine (30 μM) increased binding by some 200% above control. In the presence of glutamate and glycine all cations except Sr2+ only inhibited binding, while the stimulation produced by Sr2+ was markedly diminished. The potency of most of the divalent cations tested was increased in the presence of glutamate and glycine. In contrast, Cd2+ and Zn2+ became less potent, while the potency of Hg2+ did not change. Thus, it appears that cations regulate the function of the N-methyl-D-aspartate receptor/ ionophore complex by interacting with at least two separate sites.

References (42)

  • H.J. Olverman et al.

    [3H]CCP, a new competitive ligand for NMDA receptors

    European J. Pharmacol.

    (1986)
  • B. Pearce et al.

    Astrocyte glutamate receptor activation promotes inositol phospholipid turnover and calcium flux

    Neurosci. Lett.

    (1986)
  • N.A. Anis et al.

    The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate

    Br. J. Pharmacol.

    (1983)
  • C.J. Carter et al.

    Ionic mechanisms implicated in the stimulation of cerebellar cyclic GMP levels by N-methyl-D-aspartate

    J. Neurochem.

    (1987)
  • E.J. Coan et al.

    Effects of phencyclidine, SKF 10047 and related psychotomimetic agents on N-methyl-D-aspartate receptor mediated synaptic responses in rat hippocampal slices

    Br. J. Pharmacol.

    (1987)
  • I.L. Crawford et al.

    Zinc in maturing rat brain: hippocampal concentration and localization

    J. Neurochem.

    (1972)
  • J.B. Fischer et al.

    Biochemical aspects of GABA/benzodiazepine receptor function

  • A.C. Foster et al.

    The novel anticonvulsant MK801 binds to the activated state of the N-methyl-D-aspartate receptor in rat brain

    Br. J. Pharmacol.

    (1987)
  • R.J. Gould et al.

    [3H]Nitrendipine-labeled calcium channels discriminate inorganic calcium agonists and antagonists

  • H. Havoundjian et al.

    The permeability of gamma-aminobutyric acid-gated chloride channels is described by the binding of a ‘cage’ convulsant, t-butylbicyclophosphoro [35S]thionate

  • J.E. Heuttner et al.

    Block of NMDA-activated current by the anticonvulsant MK-801: selective binding to open channels

  • Cited by (0)

    View full text