Modulation of glutamate release by a nitric oxide/cyclic GMP-dependent pathway

Abstract 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 μM 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.