Modulation of the NMDA Receptor by Cyanide: Enhancement of Receptor-Mediated Responses

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 280; no. 3; pp. 1341 - 1348
• Main Authors: Sun, P, Rane, S G, Gunasekar, P G, Borowitz, J L, Isom, G E
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.03.1997
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Animals; Calcium - metabolism; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - metabolism; Cyanides - pharmacology; Cytoplasmic Granules - drug effects; Cytoplasmic Granules - metabolism; Diltiazem - pharmacology; Dizocilpine Maleate - pharmacology; Magnesium - pharmacology; Membrane Potentials - drug effects; N-Methylaspartate - pharmacology; Nifedipine - pharmacology; Patch-Clamp Techniques; Potassium - metabolism; Rats; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Tetrodotoxin - pharmacology
• ISSN: 0022-3565; 1521-0103

The effect of cyanide on the N-methyl-D-aspartate (NMDA)-stimulated increase in cytosolic free calcium ([Ca ++ ] i ) was studied by microfluorescence in fura-2-loaded cerebellar granule cells. The response to NMDA was enhanced by NaCN over a concentration range of 20 to 100 μM. These concentrations of NaCN in the absence of NMDA had no effect on basal [Ca ++ ] i . In comparison, NaCN did not affect K + -depolarization-induced [Ca ++ ] i elevation. The NaCN potentiation of NMDA-evoked [Ca ++ ] i elevation was blocked by addition of Mg ++ and by the NMDA receptor antagonists 2-amino-5-phosphono-valeric acid and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine maleate. Pretreatment of the cells with pregnenolone sulfate or arachidonate, known modulators of the NMDA receptor, enhanced NaCN action. The voltage-sensitive calcium channel blockers nifedepine and diltiazem did not affect the NaCN-induced potentiation. Additionally, the NaCN action was not altered when tetrodotoxin was used to block Na + channel-mediated glutamate release. In patch-clamp studies, NaCN increased the amplitude and duration of NMDA-stimulated whole-cell currents. NaCN also enhanced the NMDA receptor response in single-channel patch-clamp experiments. In the outside-out patch recording configuration, NaCN increased the NMDA receptor channel opening frequency without affecting single-channel conductance or mean channel open time. These results indicate that cyanide interacts directly with the NMDA receptor channel complex to enhance receptor-mediated responses.