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 AAl/N‐methyl‐d‐aspartate (NMDA), AA2/quisqualate, and AA3/kainate receptor recognition sites, as well as a CaCla‐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 < 0.005 and r= 0.98, p < 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.