Homocysteic acid as a putative excitatory amino acid neurotransmitter: I. Postsynaptic characteristics at N-methyl-D-aspartate-type receptors on striatal cholinergic interneurons.
The actions of the stereoisomers of homocysteic acid (HCA) were characterized at N-methyl-D-aspartate (NMDA)-type receptors which mediate excitatory amino acid-evoked [3H]acetylcholine ([3H]ACh) release from striatal cholinergic interneurons. Like NMDA, L-HCA and D-HCA evoked the release of [3H]ACh formed from [3H]choline in striatal slices. The concentration-response curve for L-HCA was virtually superimposable on that for NMDA, yielding an equal EC50 value (56.1 microM) and maximal response. However, D-HCA was weaker, with an EC50 value of 81.1 microM, and an apparently smaller maximal response. L-HCA-evoked [3H]ACh release was inhibited by the same categories of compounds which inhibit NMDA-evoked [3H]ACh release: the divalent ion Mg2+ (IC50 = 25.8 microM); competitive NMDA antagonists 2-amino-7-phosphonoheptanoate (IC50 = 51.2 microM) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (IC50 = 20.1 microM); and the dissociative anesthetics tiletamine (IC50 = 0.59 microM) and MK-801 (IC50 = 0.087 microM). Like NMDA, L-HCA produced a tachyphylaxis in this system. Tachyphylaxis to NMDA resulted in a decrease response to L-HCA, and conversely, tachyphylaxis to L-HCA resulted in a decrease response to NMDA. The results suggest that L-HCA is an agonist at the NMDA-type receptor and may represent an endogenous ligand for this excitatory amino acid receptor.
Lehmann
J
J
Research Department, Ciba-Geigy Corp., Summit, New Jersey.
Tsai
C
C
Wood
P L
PL
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000109:Acetylcholine / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002794:Choline / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D016291:Dizocilpine Maleate; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007395:Interneurons / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D013618:Tachyphylaxis / Q000187:drug effects; D013992:Tiletamine / Q000494:pharmacology
D000596:Amino Acids; D003986:Dibenzocycloheptenes; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D006710:Homocysteine; C007956:homocysteic acid; D013992:Tiletamine; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D008274:Magnesium; D002794:Choline; D000109:Acetylcholine; C031231:2-amino-7-phosphonoheptanoic acid