title: Nitric oxide regulates c-fos expression in nucleus tractus solitarii induced by baroreceptor activation via cGMP-dependent protein kinase and cAMP response element-binding protein phosphorylation.
abstract: Activation of the arterial baroreceptors induces expression of the proto-oncogene c-fos in the nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents in the medulla oblongata. This induced expression is an intracellular event that is crucial to long-term maintenance of stable blood pressure. Using Sprague-Dawley rats maintained under propofol anesthesia, we evaluated the role and delineated the underlying molecular mechanisms of nitric oxide (NO) in this process. Baroreceptor activation induced by 30 min of sustained hypertension significantly and sequentially increased the level of cyclic GMP-dependent protein kinase I (PKG-I), phosphorylated cyclic AMP response element-binding protein (pCREB), c-fos mRNA, and Fos protein in the NTS. All of these up-regulated expressions were significantly attenuated in animals that were pretreated immediately before baroreceptor activation with bilateral microinjection into the NTS of a selective neuronal nitric-oxide synthase (nNOS) inhibitor, 7-nitroindazole (2.5 pmol), or a soluble guanylyl cyclase (sGC) inhibitor, 1-H-[1,2,4]oxadiaolo[4,3-a]quinoxalin-1-one (1 nmol). Bilateral NTS microinjection of a cell-permeable cGMP analog, 8-bromoguanosine-3',5'-cyclic monophosphate (10 nmol) significantly elevated the level of pCREB or c-fos mRNA in the NTS. On the other hand, the up-regulated CREB phosphorylation or c-fos induction evoked in the dorsomedial medulla by baroreceptor activation was significantly antagonized by NTS application of a cell-permeable cGMP antagonist, (R)p-8-bromoguanosine-3',5'-cyclic monophosphorothioate (5 nmol), or a PKG inhibitor, (8R,9S,11S)-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H,-2,7b,11a-trizadizo-benzo(a,g)cycloocta(c,d,e)-trinden-1-one (1 nmol). We conclude that NO derived from nNOS in the NTS on baroreceptor activation may participate in c-fos expression via phosphorylation of CREB in a process that engages the sGC/cGMP/PKG-I signaling cascade.
authors.affiliation: Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan, Republic of China.
authors.forename: Samuel H H
authors.initials: SH
authors.lastname: Chan
authors.forename: Kui-Fen
authors.initials: KF
authors.lastname: Chang
authors.forename: Chen-Chun
authors.initials: CC
authors.lastname: Ou
authors.forename: Julie Y H
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis* / Q000235:genetics; D017869:Cyclic GMP-Dependent Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011311:Pressoreceptors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases