[3H]MK801 binding to the NMDA receptor/ionophore complex is regulated by divalent cations: evidence for multiple regulatory sites.
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 0.01-1.0 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 microM) and glycine (30 microM) 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.
Reynolds
I J
IJ
Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.
Miller
R J
RJ
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002412:Cations / Q000494:pharmacology*; D003986:Dibenzocycloheptenes / Q000378:metabolism*; D016291:Dizocilpine Maleate; D004594:Electrophysiology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*
D000927:Anticonvulsants; D002412:Cations; D003986:Dibenzocycloheptenes; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016291:Dizocilpine Maleate