Excitatory amino acid receptor potency and subclass specificity of sulfur-containing amino acids.
The sulfur-containing amino acids, L- and D-cysteate, L-cysteine, L- and D-cysteine sulfinate, L- and D-cysteine-S-sulfate, L-cystine, L- and D-homocysteate, L- and D-homocysteine sulfinate, L-homocysteine, L-serine-O-sulfate, and taurine were tested in two excitatory amino acid receptor functional assays and in receptor binding assays designed to label specifically the AA1/N-methyl-D-aspartate (NMDA), AA2/quisqualate, and AA3/kainate receptor recognition sites, as well as a CaCl2-dependent L-2-amino-4-phosphonobutanoate site, and a putative glutamate uptake site. Agonist efficacies were determined by chick retinal excitotoxicity and stimulated sodium efflux from rat brain slices. D-Homocysteine sulfinate, L-homocysteate, and L-serine-O-sulfate had affinities most selective for the NMDA binding site, whereas the binding affinities of D-cysteate, D-cysteine sulfinate, D-homocysteate, and L-homocysteine sulfinate were less selective. However, the correlation of agonist activity sensitive to blockade by D-2-amino-7-phosphonoheptanoate or D-2-amino-5-phosphonopentanoate in the functional assays with affinity in the NMDA binding assay (r = 0.87, p less than 0.005 and r = 0.98, p less than 0.005 for excitotoxicity and sodium efflux, respectively) allows characterization of these sulfur-containing amino acids as acting at NMDA subclass receptors. L-Homocysteate, which has been found in the brain, and L-serine-O-sulfate are selective agonists and could serve as endogenous neurotransmitters at the NMDA receptor.
D000603:Amino Acids, Sulfur / Q000378:metabolism / Q000494:pharmacology*; D000613:Aminobutyrates / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002642:Chick Embryo; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D018091:Receptors, AMPA; D011955:Receptors, Drug / Q000378:metabolism; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012160:Retina / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D013570:Synaptic Membranes / Q000378:metabolism
D000603:Amino Acids, Sulfur; D000613:Aminobutyrates; D001224:Aspartic Acid; D005971:Glutamates; D018698:Glutamic Acid; D007608:Kainic Acid; D016202:N-Methylaspartate; D018091:Receptors, AMPA; D011955:Receptors, Drug; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D012964:Sodium; C012729:2-amino-4-phosphonobutyric acid