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.
Zorumski
C F
CF
Department of Psychiatry, Washington University Medical School, St. Louis, Missouri 63110.
Thio
L L
LL
Clifford
D B
DB
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