Inter-Cellular Signalling by Nitric Oxide

  • John Garthwaite
  • Eric Southam
  • Richard Morris
Part of the Altschul Symposia Series book series (ALSS, volume 2)


It has been known for many years that excitation in the central nervous system is associated with marked elevations in the levels of the second messenger, cyclic GMP (cGMP) (Drummond, 1983). These are now known to be mediated through the release of the novel messenger molecule, nitric oxide (NO), which functions as a powerful activator of the soluble form of the cGMP synthesising enzyme, guanylate cyclase (Garthwaite, 1991). NO has a number of properties which set it apart from conventional signalling molecules, not least of which is its ability to diffuse readily across membranes and so act on cellular elements located some distance from the site of its formation. As discussed below, the targets for neuronally-derived NO include other neurons and neighbouring glial cells.


Nitric Oxide NMDA Receptor Dorsal Root Ganglion Satellite Cell Excitatory Amino Acid Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Amir, S., De Blasio, E., and English, A.M., 1991, NG-monomethyl-L-arginine co-injection attenuates the thermogenic and hyperthermic effects of E2 prostaglandin microinjection into the anterior hypothalamic preoptic area in rats, Brain Res. 556: 157–160.PubMedCrossRefGoogle Scholar
  2. Bon, C., Bohme, G.A., Doble, A., Stutzmann, J-M., and Blanchard, J-C., 1992, A role for nitric oxide in long-term potentiation, Eur. J. Neurosci. 4: 420–424.PubMedCrossRefGoogle Scholar
  3. Bredt, D.S., Hwang, P.M., Glatt, C.E., 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.PubMedCrossRefGoogle Scholar
  4. Dawson, T.M., Bredt, D.S., Fotuhi, M., Hwang, P.M., and Snyder, S.H., 1991a, Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues, Proc. Natl. Acad. Sci. USA 88: 7797–7801.PubMedCrossRefGoogle Scholar
  5. Dawson, V.L., Dawson, T.M., London, E.D., Bredt, D.S., and Snyder, S.H., 1991b, Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA 88: 6368–6371.PubMedCrossRefGoogle Scholar
  6. Vente, J., Bol, J.G.J.M., Berkelmans, H.S., Schipper, J., and Steinbusch, H.M.W., 1990, Immunocytochemistry of cGMP in the cerebellum of the immature, adult, and aged rat: the involvement of nitric oxide. A microphannacological study, Eur. J. Neurosci. 2: 845–862.PubMedCrossRefGoogle Scholar
  7. Drummond, G.I., 1983, Cyclic nucleotides in the nervous system. Adv. Cyclic Nucl. Res. 15: 373–494.Google Scholar
  8. East, S.J., and Garthwaite, J., 1991, NMDA receptor activation in rat hippocampus induces cyclic GMP formation through the L-arginine-nitric oxide pathway, Neurosci. Lett. 123: 17–19.PubMedCrossRefGoogle Scholar
  9. Garthwaite, J., 1985, Cellular uptake disguises action of L-glutamate on N-methyl-D-aspartate receptors, Br. J. Pharmacol. 85: 297–307.PubMedCrossRefGoogle Scholar
  10. Garthwaite, J., 1991, Glutamate, nitric oxide and cell-cell signalling in the nervous system, Trends Neurosci. 14: 60–67.PubMedCrossRefGoogle Scholar
  11. Garthwaite, J. and Garthwaite, G., 1987, Cellular origins of cyclic GMP responses to excitatory amino acid receptor agonists in rat cerebellum in vitro, J. Neurochem. 48: 29–39.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. Hibbs, J.B., Taintor, R.R., Vavrin, Z., Granger, D.L., Drapier, J-C., Amber, I.J., and Lancaster, J.R., 1990, Synthesis of nitric oxide from a terminal guanidino nitrogen atom of L-arginine: a molecular mechanism regulating cellular proliferation that targets intracellular iron, in: “Nitric Oxide from Arginine: a Bioregulatory System, S. Moncada and E.A. Higgs, eds., Elsevier, Amsterdam, pp 189–223.Google Scholar
  14. Hope, B.T., Michael, G.J., Knigge, K.M., and Vincent, S.R., 1991, Neuronal NADPH diaphorase is a nitric oxide synthase, Proc. Natl. Acad. Sci. USA 88: 2811–2814.PubMedCrossRefGoogle Scholar
  15. Knowles, R.G., Palacios, M., Palmer, R.M.J., and Moncada, S., 1989, Formation of nitric oxide from L-arginine in the central nervous system: a transduction mechanism for stimulation of the soluble guanylate cyclase, Proc. Natl. Acad. Sci. U.S.A. 89: 5159–5162.CrossRefGoogle Scholar
  16. Kolesnikov, Y.A., Pick, C.G., and Pasternak, G.W., 1992, NG-nitro-L-arginine prevents morphine tolerance, Eur. J. Pharmacol. 221: 399–400.PubMedCrossRefGoogle Scholar
  17. Lamus, S., Marsden, P.A., Li, G.K., Tempst, P., and Michel, T., 1992, Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isofonn, Proc. Natl. Acad. Sci. USA 89: 6348–6352.CrossRefGoogle Scholar
  18. Lyons, C.R., Orloff, G.J., and Cunningham, J.M., 1992, Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line, J. Biol. Chem. 267: 6370–6374.PubMedGoogle Scholar
  19. Marin, P., Lafon-Cazal, M., and Bockaert, J., 1992, A nitric oxide-synthase activity selectively stimulated by NMDA receptors via protein kinase C activation in mouse striatal neurons, Eur. J. Neurosci. 4: 425–432.PubMedCrossRefGoogle Scholar
  20. Marietta, M.A., 1989, Nitric oxide: biosynthesis and biological significance, Trends Biochem. Sci. 14: 488–492.CrossRefGoogle Scholar
  21. Meldrum, B.S., and Garthwaite, J., 1990, Excitatory amino acid neurotoxicity and neurodegenerative disease, Trends Pharm. Sci. 11: 379–387.PubMedCrossRefGoogle Scholar
  22. Moncada, S., Palmer, R.M.J., and Higgs, E.A., 1991, Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43: 109–142.PubMedGoogle Scholar
  23. Moore, P.K., Oluyomi, A.O., Babbedge, R.C., Wallace, P., and Hart, S.L., 1991, L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse, Br. J. Pharmacol. 102: 198–202.PubMedCrossRefGoogle Scholar
  24. Morris, R., Southam, E., Braid, D.J., and Garthwaite, J., 1992, Nitric oxide may act as a messenger between dorsal root ganglion neurones and their satellite cells, Neurosci. Lett. 137: 29–32.PubMedCrossRefGoogle Scholar
  25. Nowicki, J.P., Duval, D., Poignet, H., and Scatton, B., 1991, Nitric oxide mediates neuronal death after focal cerebral ischemia in the mouse, Eur. J. Pharmacol. 204: 339–340.PubMedCrossRefGoogle Scholar
  26. O’Dell, T.J., Hawkins, R.D., Kandel, E., 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. USA 88: 11285–11289.PubMedCrossRefGoogle Scholar
  27. Pollock, J.S., Forstermann, U., Mitchell, J.A., Warner, T.D., Nakane, M., Schmidt, H.H.H.W., and Murad, F., 1991, Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells, Proc. Natl. Acad. Sci. USA 88: 10480–10484.PubMedCrossRefGoogle Scholar
  28. Rand, M.J., 1992, Nitrergic transmission: nitric oxide as a mediator of non-adrenergic, noncholinergic neuro-effector transmission, Clin. Exp. Pharmacol. Physiol. 19: 147–169.PubMedCrossRefGoogle Scholar
  29. Reiser, G., 1990a, Mechanism of stimulation of cyclic-GMP level in a neuronal cell line mediated by serotonin (5-HT3) receptors. Involvement of nitric oxide, arachidonic-acid metabolism and cytosolic Cat+, Eur. J. Biochem. 189: 547–552.PubMedCrossRefGoogle Scholar
  30. Reiser, G., 1990b, Endothelin and a Cat+ ionophore raise cyclic GMP levels in a neuronal cell line via fonnation of nitric oxide, Br. J. Pharmac. 101: 722–726.CrossRefGoogle Scholar
  31. Schmidt, H.H.H.W., Pollock, J.S., Nakane, M., Gorsky, L.D., Forstennann, U., and Murad, F., 1991, Purification of a soluble isofonn of guanylyl cyclase-activating-factor synthase, Proc. Natl. Acad. Sci. USA 88: 365–369.PubMedCrossRefGoogle Scholar
  32. Shapoval, L.N., Sagach, V.F., and Pobegailo, L.S., 1991, Nitric oxide influences ventrolateral medullary mechanisms of vasomotor control in the cat, Neurosci. Lett. 132: 47–50.PubMedCrossRefGoogle Scholar
  33. Shibuki, K., and Okada, D., 1991, Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum, Nature 349: 326–328.PubMedCrossRefGoogle Scholar
  34. Southam, E., and Garthwaite, J., 1991, Climbing fibres as a source of nitric oxide in the cerebellum, Eur. J. Neurosci. 3: 379–382.PubMedCrossRefGoogle Scholar
  35. Southam, E., East, S.J., and Garthwaite, J., 1991, Excitatory amino acid receptors coupled to the nitric oxide:cyclic GMP pathway in rat cerebellum during development, J. Neurochem. 56: 2072–2081.PubMedCrossRefGoogle Scholar
  36. Southam, E., Morris, R., and Garthwaite, J., 1992, Sources and targets of nitric oxide in rat cerebellum, Neurosci. Lett. 137: 241–244.PubMedCrossRefGoogle Scholar
  37. Togashi, H., Sakuma, I., Yoshioka, M., Kobayashi, T., Yasuda, H., Kitabatake, A., Saito, H., Gross, S.S. and Levi, R., 1992, A central nervous system action of nitric oxide in blood pressure regulation, J. Pharmacol. Exp. Therap. 262: 343–347.Google Scholar
  38. Vincent, S.R. and Kimura, H., 1992, Histochemical mapping of nitric oxide synthase in the rat brain, Neuroscience 46: 755–784.PubMedCrossRefGoogle Scholar
  39. Wood, P.L., Emmett, M.R., Rao, T.S., Cler, J., Mick, S., and Iyengar, S., 1990, Inhibition of nitric oxide synthase blocks N-methyl-D-aspartate-, quisqualate-, kainate-, harmaline-, and pentylenetetrazol-dependent increases in cerebellar cyclic GMP in vivo, J. Neurochem. 55: 346–348.PubMedCrossRefGoogle Scholar
  40. Xie, Q-W., Cho, H.J., Calaycay, J., Mumford, R.A., Swiderek, K.M., Lee, T.D., Ding, A., Troso, T., and Nathan, C., 1992, Cloning and characterization of inducible nitric oxide synthase from mouse macrophages, Science 256: 225–228.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • John Garthwaite
    • 1
  • Eric Southam
    • 1
  • Richard Morris
    • 2
  1. 1.Department of PhysiologyUniversity of LiverpoolLiverpoolUK
  2. 2.Preclinical Veterinary ScienceUniversity of LiverpoolLiverpoolUK

Personalised recommendations