Nitric oxide and GABA sub(A) receptor function in the rat cerebral cortex and cerebellar granule cells

The aim of the present work was to investigate the mechanism by which the diffusible factor nitric oxide regulates GABA sub(A) receptor function in the brain. The effect of nitric oxide on GABA sub(A) receptor function has been studied in two different neuronal preparations: rat cerebral cortex microsacs and rat cerebellum granule cells in culture. In the first case, CABA-stimulated super(36)Cl super(-) accumulation was studied as an index of GABA sub(A) receptor function. The maximal rate of GABA-stimulated super(36)Cl super(-) accumulation (V sub(max)) was reduced by treatment of microsacs with nitric oxide chemical donors such as sodium nitroprusside (-26%) and S-nitroso-acetyl-penicillamine (-11%). The greater effect of the former agent is due to an additional interference by its breakdown products. The biochemical precursor L-arginine (1 mM) produced the same V sub(max) decrease as S-nitroso-acetyl-penicillamine. This effect was reversed by a nitric oxide synthase blocker and appears truly nitric oxide mediated. The action of nitric oxide in this system does not seem to imply cyclic GMP formation. GABA sub(A) receptor function was studied by whole-cell patch-clamp in rat cerebellum granule cells in culture. In this case, L-arginine (100 mu M) profoundly reduced the Cl super(-) current elicited by 10 mu M GABA and its effect subsided following washing out. The effect of L-arginine was observed almost exclusively on the rapidly desensitizing component of the GABA-activated current. The action of L-arginine was blocked by a protein kinase G inhibitor and mimicked by its activators. Thus, it appears that this effect in these cells involves nitric oxide formation, cyclic GMP accumulation and protein kinase G-catalysed phosphorylation of GABA sub(A) receptor.