Enhancement of NMDA-mediated responses by cyanide.
The effect of cyanide on NMDA-activated ion current and MK801 binding was studied in cultured rat hippocampal neurons. In microfluorometric analysis using fura-2, removal of extracellular Mg2+ resulted in a five-fold increase in NMDA-induced peak of [Ca2+]i. One mM NaCN enhanced the peak NMDA responses in the presence, but not in the absence of extracellular Mg2+. Cyanide enhanced the immediate rise in [Ca2+]i produced by NMDA, followed over a 1-5 min period by a gradual increase of [Ca2+]i. Similar results were obtained in whole-cell patch clamp recordings from hippocampal neurons. One mM KCN enhanced the NMDA-activated current in the presence, but not in the absence of extracellular Mg2+. This effect was independent of cyanide-mediated metabolic inhibition since the recording pipette contained ATP (2 mM). In binding assays NaCN (1 mM) increased the binding affinity of [3H]MK-801 to rat forebrain membranes in the presence of Mg2+, whereas in the absence of Mg2+, NaCN did not influence binding. These results indicate that cyanide enhances NMDA-mediated Ca2+ influx and inward current by interacting with the Mg2+ block of the NMDA receptor. The effect of cyanide can be explained by an initial interaction with the Mg2+ block of the NMDA receptor/ionophore which appears to be energy-independent, followed by a gradual increase in Ca2+ influx resulting from cellular energy reserve depletion.
Patel
M N
MN
Department of Pharmacology and Toxicology, Purdue University, West Lafayette, Indiana 47907-1334.
Peoples
R W
RW
Yim
G K
GK
Isom
G E
GE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003486:Cyanides / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism
D003486:Cyanides; D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D002118:Calcium