Ionic mechanisms implicated in the stimulation of cerebellar cyclic GMP levels by N-methyl-D-aspartate.
N-Methyl-D-aspartate (NMDA) increases cyclic GMP levels in immature rat cerebellar slices incubated in magnesium-containing Krebs buffer in vitro. This effect is blocked by 2-amino-5-phosphonovalerate and by D-alpha-aminoadipate, but not by glutamic acid diethyl ester or gamma-D-glutamylaminomethylsulfonic acid, indicating specific involvement of the NMDA receptor. The response produced by NMDA is abolished by removal of calcium from the medium, proportional to the concentration of extracellular calcium, and blocked by a number of inorganic (Ni2+, Co2+, Cd2+, La3+, Mn2+) calcium antagonists. The responses to NMDA are not blocked by barium or strontium and persist when these ions are substituted for calcium in the incubation medium. The effects of NMDA are blocked by, but are not particularly sensitive to, the organic voltage-dependent calcium channel antagonists. Nifedipine (10 microM) produces partial inhibition of the effects of NMDA, which are also antagonized by high (greater than 200 microM) concentrations of diltiazem and verapamil. The effects of NMDA are tetrodotoxin insensitive but are abolished by omission of sodium from the medium and inhibited by a tetrodotoxin-insensitive sodium channel blocker, Zn2+. The results suggest that calcium channel opening is a consequence of NMDA receptor activation in this model. However, the sodium dependence of the response argues against the use of receptor-operated calcium channels, whereas the weak activity of the organic voltage-sensitive calcium channel antagonists argues either against the use of voltage-dependent calcium channels, or that those implicated in the effects of NMDA are insensitive to these agents.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000032:analysis / Q000187:drug effects*; D006152:Cyclic GMP / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D016202:N-Methylaspartate; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D015032:Zinc / Q000494:pharmacology
D001224:Aspartic Acid; D016202:N-Methylaspartate; D006152:Cyclic GMP; D009543:Nifedipine; D015032:Zinc; D002118:Calcium