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 Ca2+-depen dent glutamate release evoked by depolarization with 30 mM KCI or 1 mM 4-aminopyridine. The nitric oxide (NO) donor S-nitroso-N-acetylpenici llamine also enhanced cGMP and reduced glutamate release. In addition, the membrane-permeable analogs 8-bromoguanosine 3':5'-cyclic monophos phate (s-Br-cGMP) and N,2'-o-dibutyrylguanosine (dbcGMP) at 10 mu M al so mimic glutamate release inhibition. The reduction in glutamate rele ase was observed with no modifications in the ATP/ADP ratio, and was r eversed in the presence of the protein kinases inhibitor {N-[2-(methyl amino)ethyl]-5-isoquinoline sulfonamide, HCl} (H-8). Interestingly, hi gher concentrations of dbcGMP (I mM) abolished the inhibition observed with low concentrations although no facilitation was observed. This f inding seems to indicate the existence of a dual role for cGMP in the control of glutamate exocytosis.