Overview of the Pathway and Functions of Nitric Oxide

James F. Dillman1, Valina L. Dawson1, Ted M. Dawson1

1 John Hopkins University School Of Medicine, Baltimore, Maryland
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 10.1
DOI:  10.1002/0471140856.tx1001s00
Online Posting Date:  May, 2001
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

Nitric oxide has been recognized for years as a toxic, reactive, free radical gas, but in recent years it has been identified as having functions in a variety of metabolic and signaling pathways. NO is synthesized, by nitric oxide synthase, on demand and diffuses to the site of action where it forms noncovalent and covalent linkages with target molecules. This overview presents the pathway of NO formation and also discusses the functions of NO in the nervous, immune and vascular systems.

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • What Is NO?
  • Pathway of NO Formation by Nitric Oxide Synthase
  • Functions of NO
  • Summary
  • Figures
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Arancio, O., Kiebler, M., Lee, C.J., Lev‐Ram, V., Tsien, R.Y., Kandel, E.R., and Hawkins, R.D. 1996. Nitric oxide acts directly in the presynaptic neuron to produce long‐term potentiation in cultured hippocampal neurons. Cell 87:1025‐1035.
   Bredt, D.S. and Snyder, S.H. 1990. Isolation of nitric oxide synthetase, a calmodulin‐requiring enzyme. Proc. Natl. Acad. Sci. U.S.A. 87:682‐685.
   Bredt, D.S., Hwang, P.H., Glatt, C., Lowenstein, C., Reed, R.R., and Snyder, S.H. 1991. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P‐450 reductase. Nature 351:714‐718.
   Bult, H., Boeckxstaens, G.E., Pleckmans, P.A., Jordaens, F.H., Van Maercke, Y.M., and Herman, A.G. 1990. Nitric oxide as an inhibitory non‐adrenergic non‐cholinergic neurotransmitter. Nature 345:346‐347.
   Burnett, A.L., Lowenstein, C.J., Bredt, D.S., Chang, T.S.K., and Snyder, S.H. 1992. Nitric oxide: A physiologic mediator of penile erection. Science 257:401‐403.
   Dawson, T.M. and Snyder, S.H. 1994. Gases as biological messengers: Nitric oxide and carbon monoxide in the brain. J. Neurosci. 14:5147‐5159.
   Dawson, V.L., Dawson, T.M., London, E.D., Bredt, D.S., and Snyder, S.H. 1991. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl. Acad. Sci. U.S.A. 88:6368‐6371.
   Desai, K.M., Sessa, W.C., and Vane, J.R. 1991. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature 351:477‐479.
   Furchgott, R.F. and Zawadski, J.V. 1980. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373‐376.
   Garthwaite, J., Charles, S.L., and Chess‐Williams, R. 1988. Endothelium‐derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336:385‐388.
   Haley, J.E., Wilcox, G.L., and Chapman, P.F. 1992. The role of nitric oxide in hippocampal long‐term potentiation. Neuron 8:211‐216.
   Hibbs, J.B. Jr., Taintor, R.R., and Vavrin, Z. 1987. Macrophage cytotoxicity: Role for L‐arginine deaminase and imino nitrogen oxidation to nitrite. Science 235:473‐476.
   Huang, P.L., Dawson, T.M., Bredt, D.S., Snyder, S.H., and Fishman, M.C. 1993. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75:1273‐1286.
   Huang, Z., Huang, P.L., Panahian, N., Dalkara, T., Fishman, M.C., and Moskowitz, M.A. 1994. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265:1883‐1885.
   Huang, P.L., Huang, Z.H., Mashimo, H., Bloch, K.D., Moskowitz, M.A., Bevan, J.A., and Fishman, M.C. 1995. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377:239‐242.
   Iadecola, C. 1997. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci. 20:132‐139.
   Ignarro, L.J., Buga, G.M., Wood, K.S., Bryns, R.E., and Chaudhuri, G. 1987. Endothelium‐derived relaxing factor produced and released from artery and vein is nitric oxide. Proc. Natl. Acad. Sci. U.S.A. 84:9265‐9269.
   Jaffrey, S.R. and Snyder, S.H. 1995. Nitric oxide: A neural messenger. Annu. Rev. Cell Dev. Biol. 11:417‐440.
   MacMicking, J.D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D.S., Trumbauer, M., Stevens, K., Xie, Q.W., Sokol, K., Hutchinson, N., Chen, H., and Mudgett, J.S. 1995. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641‐650.
   Marletta, M.A. 1994. Nitric oxide synthase: Aspects concerning structure and catalysis. Cell 78:927‐930.
   Moncada, S. and Higgs, A. 1993. The L‐arginine‐nitric oxide pathway. N. Engl. J. Med. 329:2002‐2012.
   Nathan, C. and Xie, Q.‐W. 1994. Nitric oxide synthases: Roles, tolls, and controls. Cell 78:915‐918.
   Nelson, R.J., Demas, G.E., Huang, P.L., Fishman, M.C., Dawson, V.L., Dawson, T.M., and Snyder, S.H. 1995. Behavioral abnormalities in male mice lacking neuronal nitric oxide synthase. Nature 378:383‐385.
   O'Dell, T.J., Hawkins, R.D., Kandel, E.R., and Arancio, O. 1991. Tests of the roles of two diffusible substances in long‐term potentiation: Evidence for nitric oxide as a possible early retrograde messenger. Proc. Natl. Acad. Sci. U.S.A. 88:11285‐11289.
   Palmer, R.M.J., Ferrige, A.G., and Moncada, S. 1987. Nitric oxide release accounts for the biological activity of endothelium‐derived relaxing factor. Nature 327:524‐526.
   Rajfer, J., Aronson, W.J., Bush, P.A., Dorey, F.J., and Ignarro, L.J. 1992. Nitric oxide as a mediator of the corpus cavernosum in response to nonadrenergic noncholinergic transmission. N. Engl. J. Med. 326:90‐94.
   Schmidt, H.H.H.W. and Walter, U. 1994. NO at work. Cell 78:919‐925.
   Schuman, E.M. and Madison, D.V. 1991. A requirement for the intercellular messenger nitric oxide in long‐term potentiation. Science 254:1503‐1506.
   Son, H., Hawkins, R.D., Martin, K., Kiebler, M., Huang, P.L., Fishman, M.C., and Kandel, E.R. 1996. Long‐term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase. Cell 87:1015‐1023
   Wei, X.‐Q., Charles, I.G., Smith, A., Ure, J., Feng, G.‐J., Huang, F.‐P., Xu, D., Muller, W., Moncada, S., and Liew, F.Y. 1995. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375:408‐411.
Key References
   Bredt et al., 1991. See above.
   Reports the initial cloning of nitric oxide synthase, specifically the neuronal isoform, and led to the understanding of the functional domains of the enzyme.
   Furchgott and Zawadski, 1980. See above
   Reports the role for an endothelium‐derived relaxing factor (EDRF) in the dilation of blood vessels, which would later be identified as nitric oxide.
   Garthwaite et al., 1988. See above.
   Initial report suggesting that nitric oxide plays a role in neuronal signaling. Subsequent reports would define nitric oxide as one of a new class of neurotransmitters.
   Hibbs et al., 1987. See above.
   Identification of a role for nitric oxide in the cytotoxic capabilities of macrophages.
   Palmer et al., 1987. See above.
   Identification of nitric oxide as the signaling molecule representing EDRF.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library