TY - JOUR
T1 - [3H]MK801 binding to the NMDA receptor/ionophore complex is regulated by divalent cations
T2 - evidence for multiple regulatory sites
AU - Reynolds, Ian J.
AU - Miller, Richard J.
N1 - Funding Information:
ported by Public Health Service Grants DA02121, DA 02575, MH 40165, grants from Miles and Marion Pharmaceuticals to R.J.M., and by a grant from the Scottish Rite Schizophrenia Research Program NMJ (U.S.A.) to I.J.R. and R.J.M.
PY - 1988/6/22
Y1 - 1988/6/22
N2 - 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.
AB - 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.
KW - Ca
KW - Excitatory amino acid
KW - Glutamate receptors
KW - Glycine
KW - MK801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine maleate)
KW - Mg
KW - Zn
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U2 - 10.1016/0014-2999(88)90697-8
DO - 10.1016/0014-2999(88)90697-8
M3 - Article
C2 - 2843387
AN - SCOPUS:0023819164
VL - 151
SP - 103
EP - 112
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1
ER -