NITRIC-OXIDE AND GABA(A) RECEPTOR FUNCTION IN THE RAT CEREBRAL-CORTEXAND CEREBELLAR GRANULE CELLS

The aim of the present work was to investigate the mechanism by which the diffusible factor nitric oxide regulates GABA(A) receptor function in the brain. The effect of nitric oxide on GABA(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, GABA-stimulated Cl-36(-) accumulation was studied as an in dex of GABA(A) receptor function. The maximal rate of GABA-stimulated Cl-36(-) accumulation (V-max) was reduced by treatment of microsacs wi th nitric oxide chemical donors such as sodium nitroprusside (-26%) an d S-nitroso-acetyl-penicillamine (-11%). The greater effect of the for mer agent is due to an additional interference by its breakdown produc ts. The biochemical precursor L-arginine (1 mM) produced the same V-ma x decrease as S-nitroso-acetyl-penicillamine. This effect was reversed by a nitric oxide synthase blocker and appears truly nitric oxide med iated. The action of nitric oxide in this system does not seem to impl y cyclic GMP formation. GABA(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- current elicite d by 10 mu M GABA and its effect subsided following washing out. The e ffect of L-arginine was observed almost exclusively on the rapidly des ensitizing component of the GABA-activated current. The action of L-ar ginine 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(A) receptor. Copyright (C) 1996 IBRO .