Hostname: page-component-8448b6f56d-dnltx Total loading time: 0 Render date: 2024-04-25T05:56:41.728Z Has data issue: false hasContentIssue false
  • English
  • Français

Second messenger systems as sites of drug action

Published online by Cambridge University Press:  05 December 2011

W. C. Bowman
W. C. Bowman
Affiliation:
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow G1 1XW, U.K.
Get access

Synopsis:

Transmembrane signalling from cell surface receptors occurs by two broad mechanisms: (i) the rapid (ms) direct opening of an ion channel, where the ion channel is a component of the receptor complex (e.g. the nicotinic acetylcholine receptor); and (ii) the more slow (s) modulation of a membrane enzyme or more distant ion channel. Most of the examples of this second mechanism involve a GTP-binding protein or so–called G-protein, and the production of a second messenger. The production of nitric oxide is a special case in that it is eventually produced as a result of the activity of the second messenger ïnositol trisphosphate. The nitric oxide then diffuses into a second cell to give rise to the production of an additional ‘second’ messenger, cyclic GMP.

All of the surface receptors themselves exist as a number of subtypes. Additionally, most of the components of the second messenger systems – G-proteins, adenylyl cyclase, guanylyl cyclase, phosphoinositidase, C, inositol trisphosphate receptors, protein kinase A, protein kinase G, protein kinase C, cyclic nucleotide phosphodiesterases, and the enzymes involved in phosphatidylinositol resynthesis – occur in a number of isoforms. Furthermore, all the enzymes are controlled in their activity by a number of co-factors and other modulators. This diversity provides the potential for selective drug action, a potential which is already being exploited and which will be increasingly so in the near future.

Type
Research Article
Information
Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences , Volume 99 , Issue 1-2: The Advancement of Drug Discovery , 1992 , pp. 1 - 17
Copyright
Copyright © Royal Society of Edinburgh 1992

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Beavo, J. A., & Reifsnyder, D. H., 1990. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends in Pharmacological Sciences, 11, 150–5.Google Scholar
Berridge, M. J., 1985. The molecular basis of communication within the cell. Scientific American 253, 124–34.Google Scholar
Berridge, M. J., 1987. Inositol trisphosphate and diacylglycerol: two interacting second messengers. Annual Reviews of Biochemistry 56, 159–93.CrossRefGoogle ScholarPubMed
Berridge, M. J., Cobbold, P. H., & Cuthbertson, K. S. R., 1988. Spatial and temporal aspects of cell signalling. Philosophical Transactions of the Royal Society of London, Series B. Biological Sciences 320, 325–43.Google ScholarPubMed
Bevan, S., & Wood, J. N., 1987. Arachidonic acid metabolites as second messengers. Nature 328, 20.CrossRefGoogle ScholarPubMed
Billah, M. M., & Canthes, J. C., 1990. The regulation and cellular function of phosphatidylcholine hydrolysis. Biochemical Journal 269, 281–91.CrossRefGoogle Scholar
Bourne, H. R., Sanders, D. A., & McCormick, F., 1990. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348, 125–32.CrossRefGoogle ScholarPubMed
Bredt, D. S., Hwang, P. M., Glatt, C. E., Lowenstein, C., Reed, R. R., & Snyder, S. H., 1991. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P–450 reductase. Nature 351, 714–18.CrossRefGoogle ScholarPubMed
Chang, M-s., Lowe, D. G., Lewis, M., Hellmiss, R., Chen, E., & Goeddel, D. V., 1989. Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases. Nature 341, 68–70.CrossRefGoogle ScholarPubMed
Cho-Chung, Y. S., Clair, T., Tortora, G., & Yokozaki, H., 1991. Role of site-selective cAMP analogs in the control and reversal of malignancy. Pharmacology & Therapeutics 50, 1–34.CrossRefGoogle ScholarPubMed
Cobbold, P. M., Dixon, J., Sanchez-Bueno, A., Woods, N., Daly, M., & Cuthbertson, R., 1990. Receptor control of calcium transients. In Transmembrane signalling, intracellular messengers and implications for drug development, pp. 185–206, ed. Nahorski, S. R., Chichester: John Wiley & Sons.Google Scholar
Corda, D., Luini, A., & Garattini, S., 1990. Selectivity of action can be achieved with compounds acting at second messenger targets. Trends in Pharmacological Sciences 11, 471–73.Google Scholar
Furchgott, R. F., & Vanhoutte, P. M., 1989. Endothelium-derived relaxing and contracting factors. Federation of American Societies of Experimental Biology Journal 3, 2007–18.Google Scholar
Garthwaite, J., Charles, S. L., & Chess-Williams, R., 1988. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336, 385–88.Google Scholar
Gaw, A. J., Aberdeen, J., Humphrey, P. P. A., Wadsworth, R. M., & Burnstock, G., 1991. Relaxation of sheep cerebral arteries by vasoactive intestinal polypeptide and neurogenic stimulation: inhibition by L-NG-monomethylarginine in endothelium-denuded vessels. British Journal of Pharmacology 102, 567–72.Google Scholar
Gillespie, J. S., Liu, X., & Martin, W., 1989. The effects of L-arginine and NG-monomethyl L-arginine on the response of the rat anococcygeus to NANC nerve stimulation. British Journal of Pharmacology 98, 1080–2.CrossRefGoogle ScholarPubMed
Gray, P. T. A., 1988. Oscillations of free cytosolic calcium evoked by cholinergic and catecholaminergic agonists in rat parotid acinar cells. Journal of Physiology 406, 35–53.Google Scholar
Hall, Z. W., 1987. Three of a kind: the β-adrenergic receptor, the muscarinic acetylcholine receptor, and rhodopsin. Trends in Neurosciences 10, 99–101.CrossRefGoogle Scholar
Hardie, D. G., 1991. Biochemical messengers. London: Chapman & Hall.Google Scholar
Hoffman, M., 1991. A new role for gases: neurotransmission. Science 252, 1788.Google Scholar
Jackson, T., 1991. Structure and function of G-protein coupled receptors. Pharmacology & Therapeutics 50, 425–42.CrossRefGoogle ScholarPubMed
Jastorff, B., Hoppe, J., & Morr, M., 1979. A model for the chemical interactions of adenosine 3′, 5′monophosphate with the R subunit of protein kinase type I. European Journal of Biochemistry 101, 555–61.Google Scholar
Levitzki, D., 1988. Transmembrane signalling to adenylate cyclase in mammalian cells and in Saccharomyces cerevisiae. Trends in Pharmacological Sciences 13, 298–301.Google ScholarPubMed
Li, C. G., & Rand, M. J., 1989. Evidence for a role of nitric oxide in the NANC-mediated relaxations in rat anococcygeus muscle. Clinical & Experimental Pharmacology & Physiology 16, 933–8.Google Scholar
Li, C. G., & Rand, M. J., 1990. Evidence suggesting that nitric oxide (NO) mediates NANC neurotransmission in rat gastric fundus and anococcygeus muscle. Clinical & Experimental Pharmacology & Physiology 16, Suppl., 184.Google Scholar
Li, C. G., & Rand, M. J., 1991. Evidence that part of the NANC relaxant response of guinea pig trachea to electrical field stimulation is mediated by nitric oxide. British Journal of Pharmacology 102, 91–4.CrossRefGoogle ScholarPubMed
Martin, T. F. J., 1991. Receptor regulation of phosphoinositidase C. Pharmacology & Therapeutics 49, 329–45.CrossRefGoogle ScholarPubMed
Martin, W., & Gillespie, J. S., 1991. L-Arginine-derived nitric oxide: the basis of inhibitory transmission in the anococcygeus and retractor penis muscles. In ‘Novel peripheral neurotransmitters,’ ed. Bell, , C. International Encyclopedia of Pharmacology & Therapeutics, Sect. 135, pp. 65–79. New York: Pergamon Press.Google Scholar
Mollon, J., 1991. Hue and the heptahelicals. Nature 351, 696–7.CrossRefGoogle ScholarPubMed
Moncada, S., Herman, A. G., & Vanhoutte, P., 1987. Endothelium-derived relaxing factor identified as nitric oxide. Trends in Pharmacological Sciences 8, 365–8.CrossRefGoogle Scholar
Morris, A. P., Gallacher, D. V., Irvine, R. F., & Petersen, O. H., 1987. Synergism of inositol trisphosphate and tetrakisphosphate in activating Ca2+-dependent K+ channels. Nature 330, 653–5.Google Scholar
Murad, F., Mittal, C. K., Arnold, W. P., Katsuki, S., & Kimura, H., 1978. Guanylate cyclase: activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Advances in Cyclic Nucleotide Research 9, 145–58.Google ScholarPubMed
Nahorski, S. R., (ed.) 1990. Transmembrane signalling, intracellular messengers and implications for drug development. Chichester: John Wiley & Sons.Google Scholar
Nahorski, S. R., Ragan, C. I., & Challis, R. A. J., 1991. Lithium and the phosphoinositide cycle: an example of uncompetitive inhibition and its pharmacological consequences. Trends in Pharmacological Sciences 12, 297–303.CrossRefGoogle ScholarPubMed
Needleman, P., Blaine, E. H., Grenwald, J. E., Michener, M. L., Saper, C. B., Stockmann, P. T., & Tolinay, H. E., 1989. The biochemical pharmacology of atrial peptides. Annual Reviews of Pharmacology & Toxicology 29, 23–54.CrossRefGoogle ScholarPubMed
Neer, E. J., & Clapham, D. E., 1988. Roles of G protein subunits in transmembrane signalling, Nature 333, 129–34.CrossRefGoogle ScholarPubMed
Nicholson, C. D., Challiss, R. A. J., & Shahid, M., 1991. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends in Pharmacological Sciences 12, 19–27.CrossRefGoogle ScholarPubMed
Nishizuka, Y., 1984. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308, 693–8.Google Scholar
Nishizuka, Y., 1986. Studies and perspectives of protein kinase C. Science 233, 305–12.Google Scholar
Nishizuka, Y., 1988. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334, 661–5.Google Scholar
Nishizuka, Y., 1989. Studies and prospectives of the protein kinase C family for cellular regulation. Cancer 63, 1892–903.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
Olate, J., & Allende, J. E., 1991. Structure and function of G proteins. Pharmacology & Therapeutics 51, 403–20.Google Scholar
Pessin, M. S., Baldassare, J. J., & Raben, D. M., 1990. Molecular species analysis of mitogen-stimulated 1, 2-diglycerides in fibroblasts. Journal of Biological Chemistry 265, 7959–66.Google Scholar
Petersen, O. H., 1989. Does inositol tetrakisphosphate play a role in the receptor-mediated control of calcium mobilization? Cell Calcium 10, 375–83.Google Scholar
Piomelli, D., Volterra, A., Dale, N., Siegelbaum, S. A., Kandel, E. R., Schwartz, J. H., & Belardetti, F., 1987. Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature 328, 38–43.CrossRefGoogle ScholarPubMed
Polokoff, M. A., Bencen, G. H., Vacca, J. P., de Solms, S. J., Young, S. D., & Huff, J. R., 1988. Metabolism of synthetic inositol trisphosphate analogues. Journal of Biological Chemistry 263, 11922–7.CrossRefGoogle Scholar
Potter, B. V. L., 1990. Synthesis and biology of second messenger analogues. In Transmembrane signalling, intracellular messengers and implications for drug development, pp. 207–39, ed. Nahorski, S. R. Chichester: John Wiley & Sons.Google Scholar
Pyne, N. J., 1992. Guanine-nucleotide binding regulatory proteins as targets for novel drugs. Proceedings of the Royal Society of Edinburgh (this volume).CrossRefGoogle Scholar
Rooney, T. A., & Thomas, A. P., 1991. Organisation of intracellular calcium signals generated by inositol lipid-dependent hormones. Pharmacology & Therapeutics 49, 223–38.Google Scholar
Schramm, M., & Selinger, Z., 1984. Message transmission: receptor controlled adenylate cyclase system. Science 225, 1350–6.CrossRefGoogle ScholarPubMed
Scott, J. D., 1991. Cyclic nucleotide-dependent protein kinases. Pharmacology & Therapeutics 50, 123–45.Google Scholar
Stabel, S., & Parker, P. J., 1991. Protein kinase C. Pharmacology & Therapeutics 51, 71–96.CrossRefGoogle ScholarPubMed
Taylor, C. W., & Richardson, A., 1991. Structure and function of inositol trisphosphate receptors. Pharmacology & Therapeutics 51, 97–138.Google Scholar
Taylor, C. W., 1992. ed. Intracellular messengers and drug action. In Encyclopedia of Pharmacology & Therapeutics. New York: Pergamon Press (in press).Google Scholar
Thompson, W. J., 1991. Cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. Pharmacology & Therapeutics 51, 13–34.Google Scholar
Watson, S. P., & Abbott, A., 1992. Receptor nomenclature. Trends in Pharmacological Sciences, Supplement to Vol. 13, No. 1.Google Scholar
Wastson, S. P., & Godfrey, P. O., 1988. The role of receptor-stimulated inositol phospholipid hydrolysis in the autonomic nervous system. Pharmacology & Therapeutics 38, 387–418.Google Scholar
Yoshimasa, T., Sibley, D. R., Bouvier, M., Lefkowitz, R. J., & Caron, M. G., 1987. Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation. Nature 327, 67–70.Google Scholar