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 fiv e-fold increase in NMDA-induced peak of [Ca2+](i). One mM NaCN enhance d the peak NMDA responses in the presence, but not in the absence of e xtracellular Mg2+. Cyanide enhanced the immediate rise in [Ca2+](i) pr oduced by NMDA, followed over a 1-5 min period by a gradual increase o f [Ca2+](i). Similar results were obtained in whole-cell patch clamp r ecordings from hippocampal neurons. One mM KCN enhanced the NMDA-activ ated current in the presence, but not in the absence of extracellular Mg2+. This effect was independent of cyanide-mediated metabolic inhibi tion since the recording pipette contained ATP (2 mM). In binding assa ys NaCN (1 mM) increased the binding affinity of [H-3]MK-801 to rat fo rebrain membranes in the presence of Mg2+, whereas in the absence of M g2+, NaCN did not influence binding. These results indicate that cyani de enhances NMDA-mediated Ca2+ influx and inward current by interactin g 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 b y a gradual increase in Ca2+ influx resulting from cellular energy res erve depletion.