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L-Homocysteic acid: An endogenous excitotoxic ligand of the NMDA receptor

1987; Elsevier BV; Volume: 19; Issue: 5 Linguagem: Inglês

10.1016/0361-9230(87)90077-3

1873-2747

John W. Olney, Madelon T. Price, K.Shahid Salles, Joann Labruyere, R. Ryerson, Kathryn Mahan, Gregory E. Frierdich, Lisa Samson,

Ion channel regulation and function

L-Homocysteic acid (L-HCA) has been proposed as a natural transmitter at the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor based on recent evidence that L-HCA occurs naturally in the mammalian CNS, is released from K+ stimulated brain slices in a calcium-dependent manner and may be contained in nerve terminals located in certain brain regions that have a high density of NMDA receptors. Here we report that L-HCA potently induces a pattern of cytopathology in the ex vivo chick retina which mimics the pattern of NMDA but not kainic acid (KA) neurotoxicity. We also show that known NMDA antagonists, including Mg++, D-aminophosphonopentanoate and certain anesthetics, analgesics, and sedative hypnotics block the neurotoxic actions of L-HCA in direct proportion to their efficacy in blocking NMDA neurotoxicity. While there is a perfect correspondence between agents that block NMDA and L-HCA neurotoxicity, only a few such agents are active against KA neurotoxicity. We find that 3H-Glu binding is inhibited more potently by L-HCA (Ki =9.4 μM) than NMDA (Ki=67 μM). Moreover the patterns with which L-HCA and NMDA displace 3H-Glu binding in autoradiograms appear essentially identical. These findings are consistent with the proposal that L-HCA is an endogenous ligand at NMDA receptors.