title: Nitric oxide serves as an endogenous regulator of neuronal adenosine A1 receptor expression.
abstract: Nitric oxide (NO) radicals are produced during normal cellular function, after tissue injury, and in response to immune system activation during infection. The transformation of NO to peroxynitrite is essential for mediating some of its physiological and/or cytotoxic actions. As the expression of the adenosine A1 receptor (A1AR) is regulated by oxidative stress, we evaluated the role of NO in the regulation of A1AR expression, a G protein-coupled receptor involved in cytoprotection in the central nervous system. Administration of the NO donor, S-nitrosylpenicillamine (SNAP), to pheochromocytoma 12 (PC12) cells increased A1AR protein in a time- and dose-dependent manner, with maximal induction observed with 20 microm SNAP at 24 h. The response to SNAP was attenuated by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3 oxide (C-PTIO), and by the inhibition of nuclear factor-kappaB (NF-kappaB), implicating this transcription factor in the regulatory process. In addition SNAP also increased the degradation of Inhibitory kappaB-alpha (IkappaB-alpha), a marker of NF-kappaB activation. Furthermore, the induction of inducible nitric oxide synthase (iNOS) by lipopolysaccharide increased A1AR in PC12 cells and in mice, whereas the inhibition of NOS activity suppressed this response. We conclude that NO, via the activation of NF-kappaB, serves as an endogenous regulator of A1AR, and speculate that the induction of the A1AR could counteract the cytotoxicity of NO.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9629, USA.
authors.forename: Krishna A
authors.initials: KA
authors.lastname: Jhaveri
authors.forename: Linda A
authors.initials: LA
authors.lastname: Toth
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.forename: Vickram
authors.initials: V
authors.lastname: Ramkumar
mesh_terms: D000243:Adenosine Deaminase / Q000494:pharmacology; D000818:Animals; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D016716:PC12 Cells; D016133:Polymerase Chain Reaction; D011869:Radioligand Assay; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D043682:Receptor, Adenosine A1; D009569:Nitric Oxide; D000243:Adenosine Deaminase; D019331:NG-Nitroarginine Methyl Ester