Differential Modulation by Divalent Cations of [3H]MK‐801 Binding in Brain Synaptic Membranes

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Abstract
Endogenous divalent cations, such as Mg2+, Ca2+, and Zn2+, differentially affected the binding of (+)‐[3H]5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine maleate ([3H]MK‐801) to an ion channel associated with an N‐methyl‐D‐aspartate‐sensitive subclass of excitatory amino acid receptors in different preparations of brain synaptic membranes. Both Mg2+ and Ca2+ were weak inhibitors of the binding in membranes which had not been extensively washed (nonwashed membranes), over a concentration range effective in markedly potentiating the binding in the absence of any added stimulants in membranes which had been extensively washed, but not treated with a detergent (untreated membranes). In membranes extensively washed and treated with Triton X‐100 (Triton‐treated membranes), both cations significantly potentiated the binding in the presence of added glutamate alone. In contrast, Zn2+ was invariably active as a potent inhibitor of the binding irrespective of the membrane preparations used. In untreated membranes, Ca2+ markedly accelerated the initial association rate of [3H]MK‐801 binding without affecting the binding at equilibrium in a manner similar to that found with glycine, as well as with glutamate; Mg2+, however, facilitated the initial association rate with a concomitant reduction of the binding at equilibrium. Zn2+ was effective in accelerating the initial rapid phase of association, with the initial slow phase being delayed, and in markedly reducing the binding at equilibrium. Both Mg2+ and Ca2+ also facilitated dissociation of the bound [3H]MK‐801 and Zn2+ slowed the dissociation in untreated membranes. In the presence of Mg2+ or Ca2+, glycine was ineffective in potentiating [3H]MK‐801 binding irrespective of the membrane preparations used, whereas glutamate was an effective stimulator in Triton‐treated membranes, but not in untreated membranes. However, spermidine was still active at potentiating the binding in both membrane preparations in the presence of Mg2+ or Ca2+. These results suggest that the three different divalent cations differentially modulate the opening processes of an ion channel associated with the N‐methyl‐naspartate‐sensitive receptor through the respective mechanisms in the brain.