G Proteins and G Protein-Coupled Receptors

Overview
  • Michael A. Shetzline
  • Marc G. Caron
Part of the Endocrine Updates book series (ENDO, volume 17)

Abstract

Cells live in a constantly changing milieu. The structure and biochemical nature of this environment is dynamic and in order for normal cellular function to proceed in a manner appropriate for the benefit of the organism, cells must be able to access this changing information. The biochemical mediators of this information exchange are cell surface receptors. Receptors transduce information from the extracellular space to the intracellular compartment. This process involves the following steps: receptor activation, G protein coupling, and second messenger generation. Equally important in cell signaling is the termination of this signal including desensitization, internalization and resensitization. All these steps represent potential regulatory checkpoints and possible targets for therapeutic intervention. Cell surface receptors include G protein-coupled receptors (GPCRs), as well as, ion channels and enzyme-linked receptors. GPCRs are responsible for physiological responses as diverse as visual perception, neurotransmission, cell growth and cell differentiation.

Keywords

Focal Adhesion Kinase Adenylyl Cyclase Adrenergic Receptor Intracellular Loop Nephrogenic Diabetes Insipidus 
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.

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References

  1. 1.
    Alewijnse, A. E., Timmerman, H., Jacobs, E. H., Smit, M. J., Roovers, E., Cotecchia, S. and Leurs, R. 2000 The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H(2) receptor. Mol Pharmacol 57, 890–8.PubMedGoogle Scholar
  2. 2.
    Barak, L. S., Oakley, R. H., Laporte, S. A. and Caron, M. G. 2001 Constitutive arrestinmediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus. Proc Natl Acad Sci U S A 98, 93–98.PubMedCrossRefGoogle Scholar
  3. 3.
    Bargmann, C. I. 1998 Neurobiology of the Caenorhabditis elegans genome. Science 282, 2028–33.PubMedCrossRefGoogle Scholar
  4. 4.
    Benovic, J. L., Kuhn, H., Weyand, I., Codina, J., Caron, M. G. and Lefkowitz, R. J. 1987 Functional desensitization of the isolated beta-adrenergic receptor by the betaadrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48kDa protein). Proc Natl Acad Sci U S A 84, 8879–82.PubMedCrossRefGoogle Scholar
  5. 5.
    Buck, J., Sinclair, M. L., Schapal, L., Cann, M. J. and Levin, L. R. 1999 Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc Natl Acad Sci U S A 96, 79–84.PubMedCrossRefGoogle Scholar
  6. 6.
    Bunemann, M., Lee, K. B., Pals-Rylaarsdam, R., Roseberry, A. G. and Hosey, M. M. 1999 Desensitization of G-protein-coupled receptors in the cardiovascular system. Annu Rev Physiol 61, 169–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., Richardson, J. A., Williams, S. C., Xiong, Y., Kisanuki, Y., Fitch, T. E., Nakazato, M., Hammer, R. E., Saper, C. B. and Yanagisawa, M. 1999 Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–51.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen, W. J., Goldstein, J. L. and Brown, M. S. 1990 NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor.J Biol Chem 265, 31.Google Scholar
  9. 9.
    Claing, A., Perry, S. J., Achiriloaie, M., Walker, J. K., Albanesi, J. P., Lefkowitz, R. J. and Premont, R. T. 2000 Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity. Proc Natl Acad Sci U S A 97, 1119–1124.PubMedCrossRefGoogle Scholar
  10. 10.
    Clapham, D. E. and Neer, E. J. 1997 G protein beta gamma subunits. Annu Rev Pharmacol Toxicol 37, 167–203.PubMedCrossRefGoogle Scholar
  11. 11.
    De Vries, L., Mousli, M., Wurmser, A. and Farquhar, M. G. 1995 GAIP, a protein that specifically interacts with the trimeric G protein G alpha i3, is a member of a protein family with a highly conserved core domain. Proc Natl Acad Sci U S A 92, 11916–20.PubMedCrossRefGoogle Scholar
  12. 12.
    De Vries, L., Zheng, B., Fischer, T., Elenko, E. and Farquhar, M. G. 2000 The regulator of G protein signaling family. Annu Rev Pharmacol Toxicol 40, 235–71.PubMedCrossRefGoogle Scholar
  13. 13.
    Doupnik, C. A., Davidson, N., Lester, H. A. and Kofuji, P. 1997 RGS proteins reconstitute the rapid gating kinetics of gbetagamma-activated inwardly rectifying K+ channels. Proc Natl Acad Sci U S A 94, 10461–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Feighner, S. D., Tan, C. P., McKee, K. K., Palyha, O. C., Hreniuk, D. L., Pong, S. S., Austin, C. P., Figueroa, D., MacNeil, D., Cascieri, M. A., Nargund, R., Bakshi, R., Abramovitz, M., Stocco, R., Kargman, S., O’Neill, G., Van Der Ploeg, L. H., Evans, J., Patchett, A. A., Smith, R. G. and Howard, A. D. 1999 Receptor for motilin identified in the human gastrointestinal system. Science 284, 2184–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Ferguson, S. S., Downey, W. E., 3rd, Colapietro, A. M., Barak, L. S., Menard, L. and Caron, M. G. 1996 Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science 271, 363–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Ferguson, S. S., Menard, L., Barak, L. S., Koch, W. J., Colapietro, A. M. and Caron, M. G. 1995 Role of phosphorylation in agonist-promoted beta 2-adrenergic receptor sequestration. Rescue of a sequestration-defective mutant receptor by beta ARK1. J Biol Chem 270, 24782–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Ferguson, S. S., Zhang, J., Barak, L. S. and Caron, M. G. 1998 Molecular mechanisms of G protein-coupled receptor desensitization and resensitization. Life Sci 62, 1561–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Freedman, N. J. and Lefkowitz, R. J. 1996 Desensitization of G protein-coupled receptors. Recent Prog Horm Res 51, 319–51.PubMedGoogle Scholar
  19. 19.
    Gautam, N., Downes, G. B., Yan, K. and Kisselev, O. 1998 The G-protein betagamma complex. Cell Signal 10, 447–55.PubMedCrossRefGoogle Scholar
  20. 20.
    Goodman, O. B., Jr., Krupnick, J. G., Santini, F., Gurevich, V. V., Penn, R. B., Gagnon, A. W., Keen, J. H. and Benovic, J. L. 1996 Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2- adrenergic receptor. Nature 383, 447–50.PubMedCrossRefGoogle Scholar
  21. 21.
    Gutkind, J. S. 2000 Regulation of Mitogen-Activated Protein Kinase Signaling Networks by G Protein-Coupled Receptors. Sciences STKE: stke.sciencemag.org/cgi/content/full/OC_sigtrans;2000/40/rel, 1–13.Google Scholar
  22. 22.
    Hamm, H. E. 1998 The many faces of G protein signaling. J Biol Chem 273, 669–72.PubMedCrossRefGoogle Scholar
  23. 23.
    Hellmich, M. R., Rui, X. L., Hellmich, H. L., Fleming, R. Y., Evers, B. M. and Townsend, C. M., Jr. 2000 Human colorectal cancers express a constitutively active cholecystokinin-B/Gastrin receptor that stimulates cell growth [In Process Citation]. J Biol Chem 275, 32122–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Hepler, J. R., Berman, D. M., Gilman, A. G. and Kozasa, T. 1997 RGS4 and GAIP are GTPase-activating proteins for Gq alpha and block activation of phospholipase C beta by gamma-thio-GTP-Gq alpha. Proc Natl Acad Sci U S A 94, 428–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Hildebrandt, J. D. 1997 Role of subunit diversity in signaling by heterotrimeric G proteins. Biochem Pharmacol 54, 325–39.PubMedCrossRefGoogle Scholar
  26. 26.
    Kieselbach, T., Irrgang, K. D. and Ruppel, H. 1994 A segment corresponding to amino acids Va1170-Arg182 of bovine arrestin is capable of binding to phosphorylated rhodopsin. Eur J Biochem 226, 87–97.PubMedCrossRefGoogle Scholar
  27. 27.
    Kilduff, T. S. and Peyron, C. 2000 The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23, 359–65.PubMedCrossRefGoogle Scholar
  28. 28.
    Krueger, K. M., Daaka, Y., Pitcher, J. A. and Lefkowitz, R. J. 1997 The role of sequestration in G protein-coupled receptor resensitization. Regulation of beta2-adrenergic receptor dephosphorylation by vesicular acidification. J Biol Chem 272, 5–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Laporte, S. A., Oakley, R. H., Holt, J. A., Barak, L. S. and Caron, M. G. 2000 The interaction of beta-arrestin with the AP-2 adaptor is required for the clustering of beta 2adrenergic receptor into clathrin-coated pits. J Biol Chem 275, 23120–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Laporte, S. A., Oakley, R. H., Zhang, J., Holt, J. A., Ferguson, S. S., Caron, M. G. and Barak, L. S. 1999 The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci U S A 96, 3712–3717.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee, D. K., George, S. R., Evans, J. F., Lynch, K. R. and O’Dowd, B. F. 2001 Orphan G protein-coupled receptors in the CNS. Curr Op Pharmacol 1, (in press).Google Scholar
  32. 32.
    Lefkowitz, R. J. 1993 G protein-coupled receptor kinases. Cell 74, 409–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Lefkowitz, R. J. 1993 G-protein-coupled receptors. Turned on to ill effect. Nature 365, 603–4.Google Scholar
  34. 34.
    Lefkowitz, R. J. 2000 The superfamily of heptahelical receptors. Nat Cell Biol 2, E133–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Lefkowitz, R. J., Hausdorff, W. P. and Caron, M. G. 1990 Role of phosphorylation in desensitization of the beta-adrenoceptor. Trends Pharmacol Sci 11, 190–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Lefkowitz, R. J., Pitcher, J., Krueger, K. and Daaka, Y. 1998 Mechanisms of betaadrenergic receptor desensitization and resensitization. Adv Pharmacol 42, 416–20.PubMedCrossRefGoogle Scholar
  37. 37.
    Lohse, M. J., Andexinger, S., Pitcher, J., Trukawinski, S., Codina, J., Faure, J. P., Caron, M. G. and Lefkowitz, R. J. 1992 Receptor-specific desensitization with purified proteins. Kinase dependence and receptor specificity of beta-arrestin and arrestin in the beta 2-adrenergic receptor and rhodopsin systems. J Biol Chem 267, 8558–64.PubMedGoogle Scholar
  38. 38.
    Lohse, M. J., Benovic, J. L., Codina, J., Caron, M. G. and Lefkowitz, R. J. 1990 betaArrestin: a protein that regulates beta-adrenergic receptor function. Science 248, 1547–50.Google Scholar
  39. 39.
    Miller, K., Shipman, M., Trowbridge, I. S. and Hopkins, C. R. 1991 Transferrin receptors promote the formation of clathrin lattices. Cell 65, 621–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Morris, A. J. and Malbon, C. C. 1999 Physiological regulation of G protein-linked signaling. Physiol Rev 79, 1373–430.PubMedGoogle Scholar
  41. 41.
    Needham, L. K. and Rozengurt, E. 1998 Galphal2 and Galphal3 stimulate Rho-dependent tyrosine phosphorylation of focal adhesion kinase, paxillin, and p130 Crkassociated substrate. J Biol Chem 273, 14626–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Neer, E. J. 1995 Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80, 249–57.PubMedCrossRefGoogle Scholar
  43. 43.
    Offermanns, S., Mancino, V., Revel, J. P. and Simon, M. I. 1997 Vascular system defects and impaired cell chemokinesis as a result of Galphal3 deficiency. Science 275, 533–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Ohno, H., Stewart, J., Fournier, M. C., Bosshart, H., Rhee, I., Miyatake, S., Saito, T., Gallusser, A., Kirchhausen, T. and Bonifacino, J. S. 1995 Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science 269, 1872–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Palczewski, K., Kumasaka, T., Hori, T., Behnke, C. A., Motoshima, H., Fox, B. A., Le Trong, I., Teller, D. C., Okada, T., Stenkamp, R. E., Yamamoto, M. and Miyano, M. 2000 Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289, 739–45.Google Scholar
  46. 46.
    Paschke, R. and Ludgate, M. 1997 The thyrotropin receptor in thyroid diseases. N Engl J Med 337, 1675–81.PubMedCrossRefGoogle Scholar
  47. 47.
    Premont, R. T., Inglese, J. and Lefkowitz, R. J. 1995 Protein kinases that phosphorylate activated G protein-coupled receptors. Faseb J 9, 175–82.PubMedGoogle Scholar
  48. 48.
    Premont, R. T., Matsuoka, I., Mattei, M. G., Pouille, Y., Defer, N. and Hanoune, J. 1996 Identification and characterization of a widely expressed form of adenylyl cyclase. J Biol Chem 271, 13900–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Rens-Domiano, S. and Hamm, H. E. 1995 Structural and functional relationships of heterotrimeric G-proteins. Faseb J 9, 1059–66.PubMedGoogle Scholar
  50. 50.
    Rhee, S. G. and Bae, Y. S. 1997 Regulation of phosphoinositide-specific phospholipase C isozymes. J Biol Chem 272, 15045–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Schmid, S. L. 1997 Clathrin-coated vesicle formation and protein sorting: an integrated process. Annu Rev Biochem 66, 511–48.PubMedCrossRefGoogle Scholar
  52. 52.
    Shenker, A., Laue, L., Kosugi, S., Merendino, J. J., Minegishi, T. and Cutler, G. B. 1993 A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365, 652–4.PubMedCrossRefGoogle Scholar
  53. 53.
    Simonds, W. F. 1999 G protein regulation of adenylate cyclase. Trends Pharmacol Sci 20, 66–73.PubMedCrossRefGoogle Scholar
  54. 54.
    Snow, B. E., Krumins, A. M., Brothers, G. M., Lee, S. F., Wall, M. A., Chung, S., Mangion, J., Arya, S., Gilman, A. G. and Siderovski, D. P. 1998 A G protein gamma subunit-like domain shared between RGS11 and other RGS proteins specifies binding to Gbeta5 subunits. Proc Natl Acad Sci U S A 95, 13307–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Sondek, J., Bohm, A., Lambright, D. G., Hamm, H. E. and Sigler, P. B. 1996 Crystal structure of a G-protein beta gamma dimer at 2.1A resolution. Nature 379, 369–74.PubMedCrossRefGoogle Scholar
  56. 56.
    Sunahara, R. K., Tesmer, J. J., Gilman, A. G. and Sprang, S. R. 1997 Crystal structure of the adenylyl cyclase activator Gsalpha. Science 278, 1943–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Tesmer, J. J., Sunahara, R. K., Gilman, A. G. and Sprang, S. R. 1997 Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science 278, 1907–16.PubMedCrossRefGoogle Scholar
  58. 58.
    Tesmer, J. J., Sunahara, R. K., Johnson, R. A., Gosselin, G., Gilman, A. G. and Sprang, S. R. 1999 Two-metal-Ion catalysis in adenylyl cyclase. Science 285, 756–60.PubMedCrossRefGoogle Scholar
  59. 59.
    Tsuga, H., Kameyama, K., Haga, T., Kurose, H. and Nagao, T. 1994 Sequestration of muscarinic acetylcholine receptor m2 subtypes. Facilitation by G protein-coupled receptor kinase (GRK2) and attenuation by a dominant-negative mutant of GRK2. J Biol Chem 269, 32522–7.PubMedGoogle Scholar
  60. 60.
    Vaughan, M. 1998 Signaling by heterotrimeric G proteins minireview series. J Biol Chem 273, 667–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Venter, J. C., et al. 2001 The Sequence of the Human Genome. Science 291, 1304–1351.PubMedCrossRefGoogle Scholar
  62. 62.
    von Zastrow, M. and Kobilka, B. K. 1994 Antagonist-dependent and -independent steps in the mechanism of adrenergic receptor internalization. Biol Chem 269, 18448–52.Google Scholar
  63. 63.
    Voyno-Yasenetskaya, T., Conklin, B. R., Gilbert, R. L., Hooley, R., Bourne, H. R. and Barber, D. L. 1994 G alpha 13 stimulates Na-H exchange. J Biol Chem 269, 4721–4.PubMedGoogle Scholar
  64. 64.
    Walker, J. K., Premont, R. T., Barak, L. S., Caron, M. G. and Shetzline, M. A. 1999 Properties of secretin receptor internalization differ from those of the beta(2)-adrenergic receptor. J Biol Chem 274, 31515–23.PubMedCrossRefGoogle Scholar
  65. 65.
    Watts, C. and Marsh, M. 1992 Endocytosis: what goes in and how? J Cell Sci 103, 1–8.PubMedGoogle Scholar
  66. 66.
    Wilden, U., Hall, S. W. and Kuhn, H. 1986 Phosphodiesterase activation by photoexcited rhodopsin is quenched when rhodopsin is phosphorylated and binds the intrinsic 48-kDa protein of rod outer segments. Proc Natl Acad Sci U S A 83, 1174–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Wilkie, T. M., Gilbert, D. J., Olsen, A. S., Chen, X. N., Amatruda, T. T., Korenberg, J. R., Trask, B. J., de Jong, P., Reed, R. R., Simon, M. I. and et al. 1992 Evolution of the mammalian G protein alpha subunit multigene family. Nat Genet 1, 85–91.PubMedCrossRefGoogle Scholar
  68. 68.
    Wu, G., Krupnick, J. G., Benovic, J. L. and Lanier, S. M. 1997 Interaction of arrestins with intracellular domains of muscarinic and alpha2-adrenergic receptors. J Biol Chem 272, 17836–42.PubMedCrossRefGoogle Scholar
  69. 69.
    Zhang, G., Liu, Y., Ruoho, A. E. and Hurley, J. H. 1997 Structure of the adenylyl cyclase catalytic core. Nature 386, 247–53.PubMedCrossRefGoogle Scholar
  70. 70.
    Zhang, J., Ferguson, S. S. G., Barak, L. S., Menard, L. and Caron, M. G. 1996 Dynamin and beta-arrestin reveal distinct mechanisms for G protein-coupled receptor internalization. J Biol Chem 271, 18302–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Michael A. Shetzline
    • 1
  • Marc G. Caron
    • 1
  1. 1.Howard Hughes Medical Institute Laboratories and Department of Cell Biology and MedicineDuke University Medical CenterDurhamUSA

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