Modulation of the NMDA receptor by cyanide: enhancement of receptor-mediated responses.
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 microM. 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.
Sun
P
P
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-1334, USA.
Rane
S G
SG
Gunasekar
P G
PG
Borowitz
J L
JL
Isom
G E
GE
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003486:Cyanides / Q000494:pharmacology*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D003486:Cyanides; D016194:Receptors, N-Methyl-D-Aspartate; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D004110:Diltiazem; D008274:Magnesium; D009543:Nifedipine; D011188:Potassium; D002118:Calcium