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Gene Review

Nos1  -  nitric oxide synthase 1, neuronal

Rattus norvegicus

Synonyms: BNOS, Bnos, Constitutive NOS, N-NOS, NC-NOS, ...
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Disease relevance of Nos1

  • The present study was carried out to specifically investigate the role of nNOS during liver cirrhosis [1].
  • Thus, reduction of uveitis symptoms correlates with the inhibition of c-NOS [2].
  • Specifically, physiological, biochemical, and molecular approaches were employed to evaluate the contribution of nNOS to the cirrhosis-related hyperdynamic circulation in CCl(4)-induced cirrhotic rats with ascites [1].
  • Taken together, these results indicate that nNOS-derived NO contributes to the development of the hyperdynamic circulation and fluid retention in cirrhosis [1].
  • Our results show that the three NOS isoforms participate in increasing NO levels after transient ischemia and suggest a biphasic and differential regulation of the expression of constitutive NOS isoforms in the rat cerebral cortex [3].

Psychiatry related information on Nos1

  • The effects of different COX and NOS inhibitors on the intestinal motor activity were tested. mRNA expression of COX-1 was not modified by inflammation, whereas mRNA expression of neuronal NOS was reduced in all indomethacin-treated rats [4].
  • BACKGROUND: Although long-term alcohol consumption impairs both endothelial nitric oxide synthase (NOS) (eNOS)-dependent and neuronal NOS (nNOS)-dependent reactivity of cerebral arterioles in male rats, the influence of sex on alcohol consumption-induced impairment of NOS-dependent cerebral vasodilation has not been examined [5].
  • Our results represent the first evidence that amyloid fragments impair constitutive NOS activity in cell-free and cellular systems, providing a possible molecular mechanism for the onset and/or maintenance of Alzheimer's disease [6].
  • Intrathecal injection of nNOS antisense oligonucleotides (nNOS-AS) inhibited the increase of Fos protein and NMDA(1A)R mRNA expression in the rat spinal cord during morphine withdrawal and decreased the scores of morphine withdrawal symptoms [7].

High impact information on Nos1

  • These results reveal a novel human nNOS promoter that confers the ability to rapidly upregulate nNOS expression in response to hypoxia with a functionally significant effect on vascular smooth muscle contraction [8].
  • Expression of nNOS in each liver cell type, whether from normal or injured liver, caused increased NO production and inhibited endothelin-1-induced contractility of perisinusoidal stellate cells [9].
  • Recombinant adenovirus (Ad) carrying the neuronal NOS gene (nNOS) targeted liver sinusoidal endothelial cells, stellate cells, and hepatocytes more efficiently than the corresponding cells in cirrhotic livers, but transduction rates were substantial even in cirrhotic animals [9].
  • We also investigated if stimulation of the nicotinic receptor increases neuronal NOS (nNOS) expression in cultured gastric myenteric ganglia [10].
  • We concluded that activation of the nicotinic receptor stimulates a Ca2+-dependent protein kinase C pathway, which in turn, upregulates nNOS mRNA expression and nNOS synthesis in the gastric myenteric plexus [10].

Chemical compound and disease context of Nos1

  • Pretreatment with 3-bromo-7-nitroindazole (7-NI) (25 mg/kg), a relatively specific inhibitor of neuronal NOS, significantly decreased contusion volume (1.27+/-0.17 mm3 [mean+/-SEM], p < 0.05) compared with that of control (2.52+/-0.35 mm3) [11].
  • Three types of NOS must be related to different stages of ischemic brain damage. nNOS may be neurotoxic in ischemia in the early phase, like iNOS in the late phase [12].
  • We also assessed the contribution of the neuronal (nNOS), the endothelial (eNOS), and the inducible (iNOS) isoforms of nitric oxide synthase (NOS) to tyrosine nitration in skeletal muscles both under normal conditions and in response to severe sepsis [13].
  • These findings indicate that the early-phase isoflurane-induced hypotension may involve nNOS as well as eNOS [14].
  • This hyperalgesia was dose-dependently and reversibly attenuated by intrathecal administration of the nonselective NO* synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (100-800 nmol) as well as by the selective neuronal NOS inhibitor ARL 17477 (30-600 nmol) [15].

Biological context of Nos1


Anatomical context of Nos1

  • This was addressed by measuring Nos1, Nos2, and Nos3 mRNA in the kidney, adrenal gland, heart, and hypothalamus of 16 ACTH-treated and 16 vehicle-treated rats as well as in 10 corticosterone-treated and 10 control rats [21].
  • CONCLUSION/INTERPRETATION: These results show that skeletal muscle NOS activity is impaired during the progression of insulin-deficient diabetes and reduced NOS activity is associated with a decreased abundance of both nNOS and eNOS proteins, which appears to involve post-transcriptional mechanisms [22].
  • After 1 week of diabetes, eNOS protein content was decreased only in the plasma membrane whereas nNOS protein abundance was not affected at this time [22].
  • Also, denervated and immediately reinnervated muscle fibers showed decreased expression of nNOS [17].
  • The ratio of NOS activity to nNOS mRNA was significantly higher in hippocampus and cerebellum of aged brain [23].

Associations of Nos1 with chemical compounds

  • In corticosterone rats, Nos2 mRNA decreased in cortex by 68+/-5% and in medulla by 62+/-6%; Nos3 mRNA by 50+/-8% in cortex, and Nos1 by 29+/-7% in medulla (all P<0.001 after Hochberg correction) [21].
  • CaV1p1 inhibited NO formation activity and NADPH oxidation of wild-type nNOS in a dose-dependent manner with an IC(50) value of 1.8 microM [16].
  • Addition of 1.0 mmol/L EDTA to the reaction decreased NOS activity to <5 pmol. mg(-1). h(-1) in afferent arterioles, glomeruli, and vasa recta (n=5 each), indicating that the NOS enzymatic activity in these segments is primarily a result of constitutive NOS [24].
  • Treatment of cirrhotic rats for 7 days with the specific nNOS inhibitor 7-nitroindazole (7-NI) normalized the low SVR and mean arterial pressure, elevated cardiac index, and reversed the positive sodium balance [1].
  • Recently, we reported nitroarginine-containing dipeptide amides (Huang, H; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. J. Med. Chem. 1999, 42, 3147.) and some peptidomimetic analogues (Huang, H; Martasek, P.; Roman, L. J.; Silverman, R.B. J. Med Chem. 2000, 43, 2938.) as potent and selective inhibitors of neuronal NOS (nNOS) [25].

Physical interactions of Nos1


Co-localisations of Nos1

  • Results of immunohistochemical studies showed that nNOS colocalized with the neuronal marker MAP-2 at all time points, whereas iNOS was initially localized to vessels, and then localized to activated microglia by 24 hours [28].

Regulatory relationships of Nos1

  • Caveolin is known to down-regulate both neuronal (nNOS) and endothelial nitric-oxide synthase (eNOS) [16].
  • Cyclical upregulated iNOS and long-term downregulated nNOS are the bases for relapse and quiescent phases in a rat model of IBD [4].
  • Inhibition of activated neuronal NOS and/or enhanced endothelial NOS activation may represent a potential therapeutic strategy for the treatment of TBI [11].
  • This suggests that inhibition of nNOS stimulates renin release but that this stimulatory effect in the long run might be depressed by the increase in blood pressure [29].
  • The immunohistochemical analysis revealed that the restored renal nNOS expression induced by chronic adrenomedullin infusion may reflect the restoration of nNOS expression in the macula densa and inner medullary collecting duct [30].

Other interactions of Nos1

  • In the present study, direct interactions of recombinant caveolin-1 with both the oxygenase and reductase domains of nNOS were demonstrated using in vitro binding assays [16].
  • Immunocytochemical studies exhibited distribution of nNOS and iNOS in cytoplasm and nucleus, and L-[3H] citrulline formation and DAF fluorescence confirmed NOS activity in both fractions [31].
  • Thus AVP specifically increases nNOS expression levels in the renal outer medulla and papilla [32].
  • Western blotting further revealed a dramatic decrease in eNOS protein expression in aged CA2/3 with no age-associated changes in nNOS, arginase I and II protein expression in any region examined [33].
  • Therefore, we mapped local mRNA and peptide/protein presence of both Ucn and the NO producing neuronal NO synthase (nNOS) [34].

Analytical, diagnostic and therapeutic context of Nos1


  1. Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis. Xu, L., Carter, E.P., Ohara, M., Martin, P.Y., Rogachev, B., Morris, K., Cadnapaphornchai, M., Knotek, M., Schrier, R.W. Am. J. Physiol. Renal Physiol. (2000) [Pubmed]
  2. Role of nitric oxide synthase isozymes in endotoxin-induced uveitis. Mandai, M., Mittag, T.W., Kogishi, J., Iwaki, M., Hangai, M., Yoshimura, N. Invest. Ophthalmol. Vis. Sci. (1996) [Pubmed]
  3. Nitric oxide and nitric oxide synthases in the fetal cerebral cortex of rats following transient uteroplacental ischemia. Gonzalez-Barrios, J.A., Escalante, B., Valdés, J., León-Chávez, B.A., Martinez-Fong, D. Brain Res. (2002) [Pubmed]
  4. Cyclical upregulated iNOS and long-term downregulated nNOS are the bases for relapse and quiescent phases in a rat model of IBD. Porras, M., Martín, M.T., Torres, R., Vergara, P. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  5. Sex difference in nitric oxide synthase-dependent dilatation of cerebral arterioles during long-term alcohol consumption. Sun, H., Mayhan, W.G. Alcohol. Clin. Exp. Res. (2005) [Pubmed]
  6. Beta-amyloid inhibits NOS activity by subtracting NADPH availability. Venturini, G., Colasanti, M., Persichini, T., Fioravanti, E., Ascenzi, P., Palomba, L., Cantoni, O., Musci, G. FASEB J. (2002) [Pubmed]
  7. NO mediated increase of Fos protein and NMDA1A R mRNA expression in rat spinal cord during morphine withdrawal. Gao, J.L., Zeng, Y.M., Zhang, L.C., Gu, J., Liu, H.F., Zhou, W.H., Yang, G.D. Acta Pharmacol. Sin. (2001) [Pubmed]
  8. Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. Ward, M.E., Toporsian, M., Scott, J.A., Teoh, H., Govindaraju, V., Quan, A., Wener, A.D., Wang, G., Bevan, S.C., Newton, D.C., Marsden, P.A. J. Clin. Invest. (2005) [Pubmed]
  9. Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension. Yu, Q., Shao, R., Qian, H.S., George, S.E., Rockey, D.C. J. Clin. Invest. (2000) [Pubmed]
  10. Nicotinic receptor mediates nitric oxide synthase expression in the rat gastric myenteric plexus. Nakamura, K., Takahashi, T., Taniuchi, M., Hsu, C.X., Owyang, C. J. Clin. Invest. (1998) [Pubmed]
  11. Role of nitric oxide in traumatic brain injury in the rat. Wada, K., Chatzipanteli, K., Busto, R., Dietrich, W.D. J. Neurosurg. (1998) [Pubmed]
  12. Time course of expression of three nitric oxide synthase isoforms after transient middle cerebral artery occlusion in rats. Niwa, M., Inao, S., Takayasu, M., Kawai, T., Kajita, Y., Nihashi, T., Kabeya, R., Sugimoto, T., Yoshida, J. Neurol. Med. Chir. (Tokyo) (2001) [Pubmed]
  13. Protein tyrosine nitration in the ventilatory muscles: role of nitric oxide synthases. Barreiro, E., Comtois, A.S., Gea, J., Laubach, V.E., Hussain, S.N. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
  14. Possible involvement of neuronal nitric oxide synthase enzyme in early-phase isoflurane-induced hypotension in rats. Ellenberger, E.A., Lucas, H.L., Mueller, J.L., Barrington, P.L., Chung, E., Ohgami, Y., Quock, R.M. Life Sci. (2004) [Pubmed]
  15. A role for spinal nitric oxide in mediating visceral hyperalgesia in the rat. Coutinho, S.V., Gebhart, G.F. Gastroenterology (1999) [Pubmed]
  16. Identification of caveolin-1-interacting sites in neuronal nitric-oxide synthase. Molecular mechanism for inhibition of NO formation. Sato, Y., Sagami, I., Shimizu, T. J. Biol. Chem. (2004) [Pubmed]
  17. Expression of different isoforms of nitric oxide synthase in experimentally denervated and reinnervated skeletal muscle. Tews, D.S., Goebel, H.H., Schneider, I., Gunkel, A., Stennert, E., Neiss, W.F. J. Neuropathol. Exp. Neurol. (1997) [Pubmed]
  18. Increased counteracting effect of eNOS and nNOS on an alpha1-adrenergic rise in total peripheral vascular resistance in spontaneous hypertensive rats. Berg, T. Cardiovasc. Res. (2005) [Pubmed]
  19. Upregulation of endothelial nitric oxide synthase maintains nitric oxide production in the cerebellum of thioacetamide cirrhotic rats. Hernández, R., Martínez-Lara, E., Del Moral, M.L., Blanco, S., Cañuelo, A., Siles, E., Esteban, F.J., Pedrosa, J.A., Peinado, M.A. Neuroscience (2004) [Pubmed]
  20. Nitric oxide produced via neuronal NOS may impair vasodilatation in septic rat skeletal muscle. Gocan, N.C., Scott, J.A., Tyml, K. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
  21. Decreased renal expression of nitric oxide synthase isoforms in adrenocorticotropin-induced and corticosterone-induced hypertension. Lou , Y.K., Wen, C., Li, M., Adams, D.J., Wang , M.X., Yang, F., Morris, B.J., Whitworth, J.A. Hypertension (2001) [Pubmed]
  22. Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats. Perreault, M., Dombrowski, L., Marette, A. Diabetologia (2000) [Pubmed]
  23. Activation of constitutive nitric oxide synthase(s) and absence of inducible isoform in aged rat brain. Jesko, H., Chalimoniuk, M., Strosznajder, J.B. Neurochem. Int. (2003) [Pubmed]
  24. Nitric oxide synthase activity and isoforms in rat renal vasculature. Mattson, D.L., Wu, F. Hypertension (2000) [Pubmed]
  25. Reduced amide bond peptidomimetics. (4S)-N-(4-amino-5-[aminoakyl]aminopentyl)-N'-nitroguanidines, potent and highly selective inhibitors of neuronal nitric oxide synthase. Hah, J.M., Roman, L.J., Martásek, P., Silverman, R.B. J. Med. Chem. (2001) [Pubmed]
  26. Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. Wong, C.S., Hsu, M.M., Chou, Y.Y., Tao, P.L., Tung, C.S. British journal of anaesthesia. (2000) [Pubmed]
  27. Cisplatin-induced inhibition of the calcium-calmodulin complex, neuronal nitric oxide synthase activation and their role in stomach distention. Jarve, R.K., Aggarwal, S.K. Cancer Chemother. Pharmacol. (1997) [Pubmed]
  28. Attenuation of nitric oxide synthase isoform expression by mild hypothermia after focal cerebral ischemia: variations depending on timing of cooling. Karabiyikoglu, M., Han, H.S., Yenari, M.A., Steinberg, G.K. J. Neurosurg. (2003) [Pubmed]
  29. Effects of long-term inhibition of neuronal nitric oxide synthase on blood pressure and renin release. Ollerstam, A., Skøtt, O., Ek, J., Persson, A.E., Thorup, C. Acta Physiol. Scand. (2001) [Pubmed]
  30. Chronic administration of adrenomedullin attenuates the hypertension and increases renal nitric oxide synthase in Dahl salt-sensitive rats. Yoshihara, F., Suga, S., Yasui, N., Horio, T., Tokudome, T., Nishikimi, T., Kawano, Y., Kangawa, K. Regul. Pept. (2005) [Pubmed]
  31. Nitric oxide synthase localization in the rat neutrophils: immunocytochemical, molecular, and biochemical studies. Saini, R., Patel, S., Saluja, R., Sahasrabuddhe, A.A., Singh, M.P., Habib, S., Bajpai, V.K., Dikshit, M. J. Leukoc. Biol. (2006) [Pubmed]
  32. Arginine vasopressin modulates expression of neuronal NOS in rat renal medulla. Martin, P.Y., Bianchi, M., Roger, F., Niksic, L., Féraille, E. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  33. Regional variations and age-related changes in nitric oxide synthase and arginase in the sub-regions of the hippocampus. Liu, P., Smith, P.F., Appleton, I., Darlington, C.L., Bilkey, D.K. Neuroscience (2003) [Pubmed]
  34. Colocalization of urocortin and neuronal nitric oxide synthase in the hypothalamus and Edinger-Westphal nucleus of the rat. Spina, M.G., Langnaese, K., Orlando, G.F., Horn, T.F., Rivier, J., Vale, W.W., Wolf, G., Engelmann, M. J. Comp. Neurol. (2004) [Pubmed]
  35. Expression of nitric oxide synthase isoforms in bone and bone cell cultures. Helfrich, M.H., Evans, D.E., Grabowski, P.S., Pollock, J.S., Ohshima, H., Ralston, S.H. J. Bone Miner. Res. (1997) [Pubmed]
  36. Neuronal nitric oxide synthase: expression in rat parietal cells. Premaratne, S., Xue, C., McCarty, J.M., Zaki, M., McCuen, R.W., Johns, R.A., Schepp, W., Neu, B., Lippman, R., Melone, P.D., Schubert, M.L. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  37. Stimulation of nitric oxide synthase in cerebral cortex due to elevated partial pressures of oxygen: an oxidative stress response. Thom, S.R., Bhopale, V., Fisher, D., Manevich, Y., Huang, P.L., Buerk, D.G. J. Neurobiol. (2002) [Pubmed]
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