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Cellular uptake disguises action of L‐glutamate on N‐methyl‐D‐aspartate receptors: With an appendix: Diffusion of transported amino acids into brain slices

1 Pharmacological properties of the guanosine 3′5′‐cyclic monophosphate (cyclic GMP) responses to excitatory amino acids and their analogues were compared in slices and dissociated cells from the developing rat cerebellum maintained in vitro. The intention was to determine the extent to which cellular uptake might influence the apparent properties of receptor‐mediated actions of these compounds. 2 In slices, the potencies of the weakly (or non‐) transported analogues, N‐methyl‐D‐aspartate (NMDA) and kainate (KA) (EC50 = 40 μM each) were higher than those of the transported amino acids, D‐ and L‐aspartate (EC50 = 250 μM and 300 μM) and D‐ and L‐glutamate (EC50 = 540 μM and 480 μM). Quisqualate (up to 300 μM) failed to increase cyclic GMP levels significantly. The sensitivity of agonist responses to the NMDA receptor antagonist, DL‐2‐amino‐5‐phosphonovalerate (APV), was in the order NMDA > L‐aspartate > L‐glutamate, KA. 3 In dissociated cells, L‐glutamate was 280 fold more potent (calculated EC50 = 1.7 μM). L‐ and D‐aspartate (calculated EC50 = 13 μM) and D‐glutamate (EC50 = 130 μM) were also more effective than in slices. The potencies of NMDA and KA were essentially unchanged. Responses to NMDA, L‐glutamate and L‐aspartate under these conditions were equally sensitive to inhibition by APV but the response to KA remained relatively resistant to this antagonist. 4 The implications of these results are that, in slices, cellular uptake is responsible for (i) the dose‐ response curves to L‐glutamate, L‐ and D‐aspartate bearing little or no relationship to the true (or relative) potencies of these amino acids; (ii) the potency of APV towards the actions of transported agonists acting at NMDA receptors being reduced and (iii) a differential sensitivity to APV of responses to L‐glutamate and L‐aspartate being created, the consequence being that a potent action of L‐glutamate on NMDA receptors is disguised. 5 These conclusions are supported by theoretical considerations relating to the diffusion of transported amino acids into brain slices, as elaborated in the Appendix.