Modulation of glutamate release by a nitric oxide/cyclic GMP-dependent pathway.
The mechanism by which changes in cyclic GMP (cGMP) regulate glutamate release was investigated in rat cerebrocortical nerve terminals. The elevation of cGMP levels by inhibition of cGMP-phosphodiesterase with 2-o-propoxy-phenyl-8-azapurin-6-one (zaprinast) reduced the Ca(2+)-dependent glutamate release evoked by depolarization with 30 mM KCl or 1 mM 4-aminopyridine. The nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine also enhanced cGMP and reduced glutamate release. In addition, the membrane-permeable analogs 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP) and N,2'-o-dibutyrylguanosine (dbcGMP) at 10 microM also mimic glutamate release inhibition. The reduction in glutamate release was observed with no modifications in the ATP/ADP ratio, and was reversed in the presence of the protein kinases inhibitor [N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide, HCl] (H-8). Interestingly, higher concentrations of dbcGMP (1 mM) abolished the inhibition observed with low concentrations although no facilitation was observed. This finding seems to indicate the existence of a dual role for cGMP in the control of glutamate exocytosis.
Sistiaga
A
A
Departamento de Bioquímica, Faculatad de Veterinaria, Universidad Complutense, Madrid, Spain.
Miras-Portugal
M T
MT
Sánchez-Prieto
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000096:biosynthesis / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D009411:Nerve Endings / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009569:Nitric Oxide; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D006162:Guanylate Cyclase; C011145:zaprinast; D006152:Cyclic GMP; D002118:Calcium