Effects of bromowillardiine and willardiine on non-N-methyl-D-aspartate receptors in postnatal rat hippocampal neurons.
The physiology and pharmacology of willardiine and bromowillardiine, structural analogues of quisqualate, were studied in cultured postnatal rat hippocampal neurons using whole-cell voltage-clamp techniques. These agonists appear to act at a shared non-N-methyl-D-aspartate (non-NMDA) receptor-channel complex and gate nonselective cationic currents. Willardiine currents desensitize rapidly and to a much greater degree than bromowillardiine currents. In addition, the brominated compound produces steady state currents that are 5 times larger than those produced by willardiine at saturation. Bromowillardiine is also a more efficacious excitotoxin, producing about 3-fold greater acute neuronal damage than willardiine at saturating concentrations. These results suggest that agonist structure affects the ability of non-NMDA agonists to induce desensitization and add support to the hypothesis that receptor desensitization serves to limit acute excitotoxicity in cultured neurons.
Department of Psychiatry, Washington University Medical School, St. Louis, Missouri 63110.
C F
CF
Zorumski
L L
LL
Thio
D B
DB
Clifford
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000200:Action Potentials / Q000187:drug effects; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D011744:Pyrimidinones; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000502:physiology; D014498:Uracil
D011744:Pyrimidinones; D011810:Quinoxalines; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C068592:5-bromowillardiine; C002872:willardiine; D014498:Uracil; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000409:Alanine