G-Proteins and GPCRs: From the Beginning

  • H. R. Bourne
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/2)


From the point of view of a participant observer, I tell the discovery stories of trimeric G-proteins and GPCRs, beginning in the 1970s. As in most such stories, formidable obstacles, confusion, and mistakes make eventual triumphs even more exciting. Because these pivotally important signaling molecules were discovered before the recombinant DNA revolution, today's well-trained molecular biologist may find it amazing that we learned anything at all.


Adenylyl Cyclase GTPase Activity Sodium Metabisulfite cAMP Synthesis Turkey Erythrocyte 
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.



I thank Thomas Sakmar, Lutz Birnbaumer, Paul Insel, Zvi Selinger, and Elliott Ross for commenting on parts of the manuscript. Mistakes, however, are clearly my own.


  1. Ahlquist R (1948) A study of the adrenergic receptors. Am J Physiol 153:586–600PubMedGoogle Scholar
  2. Aurbach GD, Fedak SA, Woodard CJ, Palmer JS, Hauser D, Troxler F (1974) Beta-adrenergic receptor: stereospecific interaction of iodinated beta-blocking agent with high affinity site. Science 186:1223–1224PubMedCrossRefGoogle Scholar
  3. Benovic JL, Kuhn H, Weyand I, Codina J, Caron MG, Lefkowitz RJ (1987) Functional desensitization of the isolated beta-adrenergic receptor by the beta-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Acad Sci USA 84:8879–8882PubMedCrossRefGoogle Scholar
  4. Benovic JL, Shorr RG, Caron MG, Lefkowitz RJ (1984) The mammalian beta 2-adrenergic receptor: purification and characterization. Biochemistry 23:4510–4518PubMedCrossRefGoogle Scholar
  5. Benovic JL, Strasser RH, Caron MG, Lefkowitz RJ (1986) Beta-adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor. Proc Natl Acad Sci USA 83:2797–2801PubMedCrossRefGoogle Scholar
  6. Bilezikian JP, Aurbach GD (1973a) A beta-adrenergic receptor of the turkey erythrocyte. I. Binding of catecholamine and relationship to adenylate cyclase activity. J Biol Chem 248:5577–5583PubMedGoogle Scholar
  7. Bilezikian JP, Aurbach GD (1973b) A beta-adrenergic receptor of the turkey erythrocyte. II. Characterization and solubilization of the receptor. J Biol Chem 248:5584–5589PubMedGoogle Scholar
  8. Bitensky MW, Miki N, Keirns JJ, Keirns M, Baraban JM, Freeman J, Wheeler MA, Lacy J, Marcus FR (1975) Activation of photoreceptor disk membrane phosphodiesterase by light and ATP. Adv Cyclic Nucleotide Res 5:213–240PubMedGoogle Scholar
  9. Bourne HR, Coffino P, Tomkins GM (1975a) Selection of a variant lymphoma cell deficient in adenylate cyclase. Science 187:750–752PubMedCrossRefGoogle Scholar
  10. Bourne HR, Coffino P, Tomkins GM (1975b) Somatic genetic analysis of cyclic AMP action: characterization of unresponsive mutants. J Cell Physiol 85:611–620PubMedCrossRefGoogle Scholar
  11. Caron MG, Srinivasan Y, Pitha J, Kociolek K, Lefkowitz RJ (1979) Affinity chromatography of the beta-adrenergic receptor. J Biol Chem 254:2923–2927PubMedGoogle Scholar
  12. Cassel D, Levkovitz H, Selinger Z (1977) The regulatory GTPase cycle of turkey erythrocyte adenylate cyclase. J Cyclic Nucleotide Res 3:393–406PubMedGoogle Scholar
  13. Cassel D, Pfeuffer T (1978) Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. Proc Natl Acad Sci USA 75:2669–2673PubMedCrossRefGoogle Scholar
  14. Cassel D, Selinger Z (1976) Catecholamine-stimulated GTPase activity in turkey erythrocyte membranes. Biochim Biophys Acta 452:538–551PubMedGoogle Scholar
  15. Cassel D, Selinger Z (1977) Mechanism of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site. Proc Natl Acad Sci USA 74:3307–3311PubMedCrossRefGoogle Scholar
  16. Cerione RA, Sibley DR, Codina J, Benovic JL, Winslow J, Neer EJ, Birnbaumer L, Caron MG, Lefkowitz RJ (1984) Reconstitution of a hormone-sensitive adenylate cyclase system. The pure beta-adrenergic receptor and guanine nucleotide regulatory protein confer hormone responsiveness on the resolved catalytic unit. J Biol Chem 259:9979–9982PubMedGoogle Scholar
  17. Coffino P, Bourne HR, Tomkins GM (1975) Somatic genetic analysis of cyclic AMP action: selection of unresponsive mutants. J Cell Physiol 85:603–610PubMedCrossRefGoogle Scholar
  18. Daniel V, Litwack G, Tomkins GM (1973) Induction of cytolysis of cultured lymphoma cells by adenosine 3′:5′-cyclic monophosphate and the isolation of resistant variants. Proc Natl Acad Sci USA 70:76–79PubMedCrossRefGoogle Scholar
  19. De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem 255:7108–7117PubMedGoogle Scholar
  20. Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E, Diehl RE et al. (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321:75–79PubMedCrossRefGoogle Scholar
  21. Farfel Z, Brickman AS, Kaslow HR, Brothers VM, Bourne HR (1980) Defect of receptor-cyclase coupling protein in pseudohypoparathyroidism. New Engl J Med 303:237–242PubMedCrossRefGoogle Scholar
  22. Fung B, Stryer L (1980) Photolyzed rhodopsin catalyzes the exchange of GTP for bound GDP in retinal rod outer segments. Proc Natl Acad Sci USA 77:2500–2504CrossRefGoogle Scholar
  23. Fung BK, Hurley JB, Stryer L (1981) Flow of information in the light-triggered cyclic nucleotide cascade of vision. Proc Natl Acad Sci USA 78:152–156PubMedCrossRefGoogle Scholar
  24. Gilman AG (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56:615–649PubMedCrossRefGoogle Scholar
  25. Godchaux W, Zimmerman WF (1979) Membrane-dependent guanine nucleotide binding and GTPase activities of soluble protein from bovine rod cell outer segments. J Biol Chem 254:7874–7884PubMedGoogle Scholar
  26. Harris BA, Robishaw JD, Mumby SM, Gilman AG (1985) Molecular cloning of complementary DNA for the alpha subunit of the G protein that stimulates adenylate cyclase. Science 229:1274–1277PubMedCrossRefGoogle Scholar
  27. Hsia Y (1965) Photochemistry of vision. In: Graham CH (ed) Vision and visual perception. Wiley, New YorkGoogle Scholar
  28. Insel PA, Bourne HR, Coffino P, Tomkins GM (1975) Cyclic AMP-dependent protein kinase: pivotal role in regulation of enzyme induction and growth. Science 190:896–898PubMedCrossRefGoogle Scholar
  29. Insel PA, Maguire ME, Gilman AG, Bourne HR, Coffino P, Melmon KL (1976) Beta adrenergic receptors and adenylate cyclase: products of separate genes? Mol Pharmacol 12:1062–1069PubMedGoogle Scholar
  30. Johnson GL, Kaslow HR, Bourne HR (1978) Genetic evidence that cholera toxin substrates are regulatory components of adenylate cyclase. J Biol Chem 253:7120–7123PubMedGoogle Scholar
  31. Kuhn H (1978) Light-regulated binding of rhodopsin kinase and other proteins to cattle photoreceptor membranes. Biochemistry 17:4389–4395PubMedCrossRefGoogle Scholar
  32. Kuhn H, Dreyer WJ (1972) Light dependent phosphorylation of rhodopsin by ATP. FEBS Lett 20:1–6PubMedCrossRefGoogle Scholar
  33. Kuhn H, McDowell JH, Leser KH, Bader S (1977) Phosphorylation of rhodopsin as a possible mechanism of adaptation. Biophys Struct Mech 3:175–180PubMedCrossRefGoogle Scholar
  34. Lefkowitz RJ (1973) Isolated hormone receptors: physiologic and clinical implications. N Engl J Med 288:1061–1066PubMedCrossRefGoogle Scholar
  35. Lefkowitz RJ (1974) Commentary. Molecular pharmacology of beta-adrenergic receptors: a status report. Biochem Pharmacol 23:2069–2076PubMedCrossRefGoogle Scholar
  36. Lefkowitz RJ, Haber E (1971) A fraction of the ventricular myocardium that has the specificity of the cardiac beta-adrenergic receptor. Proc Natl Acad Sci USA 68:1773–1777PubMedCrossRefGoogle Scholar
  37. Lefkowitz RJ, Haber E, O'Hara D (1972) Identification of the cardiac beta-adrenergic receptor protein: solubilization and purification by affinity chromatography. Proc Natl Acad Sci USA 69:2828–2832PubMedCrossRefGoogle Scholar
  38. Lefkowitz RJ, Mukherjee C, Coverstone M, Caron MG (1974) Stereospecific (3H)(minus)-alprenolol binding sites, beta-adrenergic receptors and adenylate cyclase. Biochem Biophys Res Commun 60:703–709PubMedCrossRefGoogle Scholar
  39. Levitzki A, Atlas D, Steer ML (1974) The binding characteristics and number of beta-adrenergic receptors on the turkey erythrocyte. Proc Natl Acad Sci USA 71:2773–2776PubMedCrossRefGoogle Scholar
  40. Lochrie MA, Hurley JB, Simon MI (1985) Sequence of the alpha subunit of photoreceptor G protein: homologies between transducin, ras, and elongation factors. Science 228:96–99PubMedCrossRefGoogle Scholar
  41. Londos C, Salomon Y, Lin MC, Harwood JP, Schramm M, Wolff J, Rodbell M (1974) 5′-Guanylylimidodiphosphate, a potent activator of adenylate cyclase systems in eukaryotic cells. Proc Natl Acad Sci USA 71:3087–3090PubMedCrossRefGoogle Scholar
  42. Maguire ME, Goldmann PH, Gilman AG (1974) The reaction of [3H]norepinephrine with particulate fractions of cells responsive to catecholamines. Mol Pharmacol 10:563–581Google Scholar
  43. Maguire ME, Sturgill TW, Gilman AG (1975) Frustration and adenylate cyclase. Metabolism 24:287–299PubMedCrossRefGoogle Scholar
  44. May DC, Ross EM, Gilman AG, Smigel MD (1985) Reconstitution of catecholamine-stimulated adenylate cyclase activity using three purified proteins. J Biol Chem 260:15829–15833PubMedGoogle Scholar
  45. Medynski DC, Sullivan K, Smith D, Van Dop C, Chang FH, Fung BK, Seeburg PH, Bourne HR (1985) Amino acid sequence of the alpha subunit of transducin deduced from the cDNA sequence. Proc Natl Acad Sci USA 82:4311–4315PubMedCrossRefGoogle Scholar
  46. Murayama T, Ui M (1983) Loss of the inhibitory function of the guanine nucleotide regulatory component of adenylate cyclase due to its ADP ribosylation by islet-activating protein, pertussis toxin, in adipocyte membranes. J Biol Chem 258:3319–3326PubMedGoogle Scholar
  47. Nathans J, Hogness DS (1983) Isolation, sequence analysis, and intron-exon arrangement of the gene encoding bovine rhodopsin. Cell 34:807–814PubMedCrossRefGoogle Scholar
  48. Northup JK, Sternweis PC, Smigel MD, Schleifer LS, Ross EM, Gilman AG (1980) Purification of the regulatory component of adenylate cyclase. Proc Natl Acad Sci USA 77:6516–6520PubMedCrossRefGoogle Scholar
  49. Ovchinnikov YA, Abdulaev NG, Feigina MY, Artamonov ID, Zolotarev AS, Miroshnikov AL, Martynov VL, Kostina MB, Kudelin AB, Bogachuk AS (1982) The complete amino acid sequence of visual rhodopsin. Bioorg Khim 8:1424–1427Google Scholar
  50. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745PubMedCrossRefGoogle Scholar
  51. Rall TW, Sutherland EW, Berthet J (1957) The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. J Biol Chem 224:463–475PubMedGoogle Scholar
  52. Rodbell M, Birnbaumer L, Pohl SL, Krans HMJ (1971a) The glucagon-sensitive adenyl cyclase system in plasma membranes of rat liver. V. An obligatory role of guanyl nucleotides in glucagon action. J Biol Chem 246:1877–1882PubMedGoogle Scholar
  53. Rodbell M, Krans HMJ, Pohl SL, Birnbaumer L (1971b) The glucagon-sensitive adenyl cyclase system in plasma membranes of rat liver. IV. Effects of guanyl nucleotides on binding of 125I-glucagon. J Biol Chem 246:1872–1876PubMedGoogle Scholar
  54. Ross EM, Gilman AG (1977a) Reconstitution of catecholamine-sensitive adenylate cyclase activity: interactions of solubilized components with receptor-replete membranes. Proc Natl Acad Sci USA 74:3715–3719PubMedCrossRefGoogle Scholar
  55. Ross EM, Gilman AG (1977b) Resolution of some components of adenylate cyclase necessary for catalytic activity. J Biol Chem 252:6966–6969PubMedGoogle Scholar
  56. Ross EM, Gilman AG (1980) Biochemical properties of hormone-sensitive adenylate cyclase. Annu Rev Biochem 49:533–564PubMedCrossRefGoogle Scholar
  57. Shichi H, Somers RL (1978) Light-dependent phosphorylation of rhodopsin. Purification and properties of rhodopsin kinase. J Biol Chem 253:7040–7046PubMedGoogle Scholar
  58. Shorr RG, Lefkowitz RJ, Caron MG (1981) Purification of the beta-adrenergic receptor. Identification of the hormone binding subunit. J Biol Chem 256:5820–5826PubMedGoogle Scholar
  59. Stadel JM, Nambi P, Shorr RG, Sawyer DF, Caron MG, Lefkowitz RJ (1983) Catecholamine-induced desensitization of turkey erythrocyte adenylate cyclase is associated with phosphorylation of the beta-adrenergic receptor. Proc Natl Acad Sci USA 80:3173–3177PubMedCrossRefGoogle Scholar
  60. Sutherland EW, Rall TW (1960) Formation of adenosine-3,5-phosphate (cyclic adenylate) and its relation to the action of several neurohormones or hormones. Acta Endocrinol (Copenh) 34(Suppl 50):171–174Google Scholar
  61. Tanabe T, Nukada T, Nishikawa Y, Sugimoto K, Suzuki H, Takahashi H, Noda M, Haga T, Ichiyama A, Kangawa K et al. (1985) Primary structure of the alpha-subunit of transducin and its relationship to ras proteins. Nature 315:242–245PubMedCrossRefGoogle Scholar
  62. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR (1997) Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha. GTPgammaS. Science 278:1907–1916PubMedCrossRefGoogle Scholar
  63. Wald G (1968) The molecular basis of visual excitation. Nature 219:800–807PubMedCrossRefGoogle Scholar
  64. Wheeler GL, Bitensky MW (1977) A light-activated GTPase in vertebrate photoreceptors: regulation of light-activated cyclic GMP phosphodiesterase. Proc Natl Acad Sci USA 74:4238–4242PubMedCrossRefGoogle Scholar
  65. Wilden U, Hall SW, 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 USA 83:1174–1178PubMedCrossRefGoogle Scholar
  66. Yarden Y, Rodriguez H, Wong SK, Brandt DR, May DC, Burnier J, Harkins RN, Chen EY, Ramachandran J, Ullrich A et al. (1986) The avian beta-adrenergic receptor: primary structure and membrane topology. Proc Natl Acad Sci USA 83:6795–6799PubMedCrossRefGoogle Scholar
  67. Yee R, Liebman PA (1978) Light-activated phosphodiesterase of the rod outer segment. Kinetics and parameters of activation and deactivation. J Biol Chem 253:8902–8909PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.UCSFSan FranciscoUSA

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