title: Nitric oxide depresses GABAA receptor function via coactivation of cGMP-dependent kinase and phosphodiesterase.
abstract: Nitric oxide (NO) is thought to play an essential role in neuronal processing, but the downstream mechanisms of its action remain unclear. We report here that NO analogs reduce GABA-gated currents in cultured retinal amacrine cells via two distinct, but convergent, cGMP-dependent pathways. Either extracellular application of the NO-mimetic S-nitroso-N-acetyl-penicillamine (SNAP) or intracellular perfusion with cGMP depressed GABA currents. This depression was partially blocked by a pseudosubstrate peptide inhibitor of cGMP-dependent protein kinase (PKG), suggesting both PKG-dependent and independent actions of cGMP. cAMP-dependent protein kinase (PKA) is known to enhance retinal GABA responses. 8-Bromoinosine 3',5'-cyclic monophosphate (8Br-cIMP), which activates a type of cGMP-stimulated phosphodiesterase that hydrolyzes cAMP, also significantly reduced GABA currents. 1-Methyl-3-isobutylxanthine (IBMX), a nonspecific phosphodiesterase (PDE) inhibitor, blocked both the action of 8Br-cIMP and the portion of SNAP-induced depression that was not blocked by PKG inhibition. Our results suggest that NO depresses retinal GABAA receptor function by simultaneously upregulating PKG and downregulating PKA.
authors.affiliation: Department of Ophthalmology and Visual Science, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Wexler
authors.forename: P K
authors.initials: PK
authors.lastname: Stanton
authors.forename: S
authors.initials: S
authors.lastname: Nawy
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D007289:Cyclic IMP / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D013439:Sulfhydryl Reagents / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; D011963:Receptors, GABA-A; C110881:S-nitro-N-acetylpenicillamine; D013439:Sulfhydryl Reagents; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D007289:Cyclic IMP; C088028:arginyl-lysyl-arginyl-alanyl-arginyl-lysyl-glutamic acid; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D010396:Penicillamine; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine