Different modulation of the binding to two phencyclidine (PCP) receptor subtypes: effects of N-methyl-D-aspartate agonists and antagonists.
Neurochemical studies have indicated that the dissociative anesthetics, phencyclidine (PCP) and ketamine, act as non-competitive antagonists at the excitatory amino acid, N-methyl-D-aspartate (NMDA), receptor-gated ion channel. Since the binding of PCP and related psychotomimetics, i.e. (+)-N-allylnormetazocine [+)-SKF 10047), in mammalian brain is associated with multiple receptor subtypes, their modulation by NMDA agonists and antagonists was investigated. Binding of the potent PCP analog, [3H]PCP-3-OH to the high-affinity sigma/PCP (sigma p) site and (+)-[3H]SKF 10047 to the sigma/haloperidol sensitive (sigma h) site in rat brain membranes was not affected by L-glutamate and NMDA, nor by the competitive NMDA antagonists D-2-amino-5-phosphovaleric acid (AP-5), D-2-amino-7-phosphoheptanoic acid (AP-7). However, binding of [3H]PCP-3-OH to the low-affinity PCP-selective site was enhanced by 4- to 5-fold in the presence of glutamate or NMDA and reduced in a competitive manner by AP-5. The noncompetitive NMDA antagonist, MK-801, was however a potent inhibitor of the binding to both sigma p and PCP sites labeled with [3H]PCP-3-OH. The present results indicate that the high (sigma p) and low-affinity (PCP) sites, that are distinct from the sigma h site, are affected differently by NMDA agonists and antagonists, and thus may represent different receptor domains.
Itzhak
Y
Y
Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, FL 33101.
D015763:2-Amino-5-phosphonovalerate / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001667:Binding, Competitive; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D017478:Receptors, Phencyclidine
D005971:Glutamates; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate