Both protein kinase G dependent and independent mechanisms are involved inthe modulation of glutamate release by nitric oxide in rat hippocampal nerve terminals

We compared the effects of sodium nitroprusside (SNP), and of 8-bromo guano sine 3',5'-cyclic monophosphate (8-BrcGMP), on the 4-aminopyridine (4-AP)-e voked Ca2+-dependent release of glutamate from hippocampal nerve terminals and further investigated the role of protein kinase G (PKG) in this mechani sm. SNP and 8-BrcGMP dose-dependently inhibited glutamate release, however SNP concentrations ([SNP]) > 500 mu M abolished the 4-AP evoked release, wh ereas 8-BrcGMP maximally inhibited the release by about 30%. The inhibition of glutamate release at low concentrations of SNP (less than or equal to 5 mu M) was of about 20%, and was reversed by Rp-8(4-chlorophenylthio)guanos ine-3',5'-cyclic-monophosphorotioate) (RpCPTcGMP, 50 nM), but the inhibitio n at higher concentrations (5 < SNP less than or equal to 50 mu M) was inse nsitive to the PKG inhibitor, but sensitive to [1H-(1,2,4)oxadiazolo(4,3-a) quinoxalin-1-one] (ODQ), which partially prevented the inhibition. [SNP] > 50 mu M strongly inhibited glutamate release, and this was not reversed by either inhibitor. Furthermore, [SNP] less than or equal to 50 mu M enhanced cGMP formation, and the observed effects were not related to either decrea sed Ca2+ entry or ATP/ADP levels. Our results indicate that NO/PKG is the s ignaling pathway underlying the inhibition of glutamate release at low conc entrations of NO, and imply that other NO-dependent, but PKG-independent, m echanisms are activated and have complementary roles at higher NO concentra tions. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.