Skip to main content
SpringerLink
Log in

Pharmacogenomics of G Protein-Coupled Receptor

Signaling Insights from Health and Disease

  • Protocol
Pharmacogenomics in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 448))

Summary

The identification and characterization of the processes of G protein-coupled receptor (GPCR) activation and inactivation have refined not only the study of the GPCRs but also the genomics of many accessory proteins necessary for these processes. This has accelerated progress in understanding the fundamental mechanisms involved in GPCR structure and function, including receptor transport to the membrane, ligand binding, activation and inactivation by GRK-mediated (and other) phosphorylation. The catalog of Gsα and Gβ subunit polymorphisms that result in complex phenotypes has complemented the effort to catalog the GPCRs and their variants. The study of the genomics of GPCR accessory proteins has also provided insight into pathways of disease, such as the contributions of regulator of G protein signaling (RGS) protein to hypertension and activator of G protein signaling (AGS) proteins to the response to hypoxia. In the case of the G protein-coupled receptor kinases (GRKs), identified originally in the retinal tissues that converge on rhodopsin, proteins such as GRK4 have been identified that have been subsequently associated with hypertension. Here, we review the structure and function of GPCR and associated proteins in the context of the gene families that encode them and the genetic disorders associated with their altered function. An understanding of the pharmacogenomics of GPCR signaling provides the basis for examining the GPCRs disrupted in monogenic disease and the pharmacogenetics of a given receptor system.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bargmann, C. I. (1998) Neurobiology of the Caenorhabditis elegans genome. Science. 282, 2028–33.

    Article  CAS  PubMed  Google Scholar 

  2. Pierce, K. L., Premont, R. T., and Lefkowitz, R. J. (2002) Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 3, 639–650.

    Article  CAS  PubMed  Google Scholar 

  3. Rashid, A. J., O'Dowd, B. F., and George, S. R. (2004) Minireview: diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology. 145, 2645–2652.

    Article  CAS  PubMed  Google Scholar 

  4. Libert, F., Vassart, G., and Parmentier, M. (1991) Current developments in G-protein-coupled receptors. Curr. Opin. Cell Biol. 3, 218–223.

    Article  CAS  PubMed  Google Scholar 

  5. Odowd, B. F., Nguyen, T., Lynch, K. R., et al. (1996) A novel gene codes for a putative G protein-coupled receptor with an abundant expression in brain. FEBS Lett. 394, 325–329.

    Article  CAS  Google Scholar 

  6. Civelli, O., Nothacker, H. P., Bourson, A., Ardati, A., Monsma, F., and Reinscheid, R. (1997) Orphan receptors and their natural ligands. J. Recept. Signal Transduct. Res. 17, 545–550.

    Article  CAS  PubMed  Google Scholar 

  7. Stadel, J. M., Wilson, S., and Bergsma, D. J. (1997) Orphan G protein-coupled receptors: a neglected opportunity for pioneer drug discovery. Trends Pharmacol. Sci. 18, 430–437.

    CAS  PubMed  Google Scholar 

  8. Wilson, S., Bergsma, D. J., Chambers, J. K., et al. (1998) Orphan G-protein-coupled receptors: the next generation of drug targets? Br. J. Pharmacol. 125, 1387–1392.

    Article  CAS  PubMed  Google Scholar 

  9. Sakurai, T., Amemiya, A., Ishii, M., et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior [see comments]. Cell. 92, 573–585.

    Article  CAS  PubMed  Google Scholar 

  10. Howard, A. D., McAllister, G., Feighner, S. D., et al. (2001) Orphan G-protein-coupled receptors and natural ligand discovery. Trends Pharmacol. Sci. 22, 132–140.

    Article  CAS  PubMed  Google Scholar 

  11. Thompson, M. D., Gravesandeg, K. S. V., Galczenski, H., et al. (2003) A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha. Pharmacogenetics. 13, 641–649.

    Article  CAS  PubMed  Google Scholar 

  12. Liu, X., Davis, D., and Segaloff, D. L. (1993) Disruption of potential sites for N-linked glycosylation does not impair hormone binding to the lutropin/choriogonadotropin receptor if Asn173 is left intact. J. Biol. Chem. 268, 1513–1516.

    CAS  PubMed  Google Scholar 

  13. Karpa, K. D., Lidow, M. S., Pickering, M. T., Levenson, R., and Bergson, C. (1999) N-linked glycosylation is required for plasma membrane localization of D5, but not D1, dopamine receptors in transfected mammalian cells. Mol. Pharmacol. 56, 1071–1078.

    CAS  PubMed  Google Scholar 

  14. Karnik, S. S., Ridge, K. D., Bhattacharya, S., and Khorana, H. G. (1993) Palmitoylation of bovine opsin and its cysteine mutants in COS cells. Proc. Natl. Acad. Sci. U. S. A. 90, 40–44.

    Article  CAS  PubMed  Google Scholar 

  15. Jin, H., Zastawny, R., George, S. R., and O'Dowd, B. F. (1997) Elimination of palmitoylation sites in the human dopamine D1 receptor does not affect receptor-G protein interaction. Eur. J. Pharmacol. 324, 109–116.

    Article  CAS  PubMed  Google Scholar 

  16. Ovchinnikov, Y., Abdulaev, N., and Bogachuk, A. (1988) Two adjacent cysteine residues in the C-terminal cytoplasmic fragment of bovine rhodopsin are palmitoylated. FEBS Lett. 230, 1–5.

    Article  CAS  PubMed  Google Scholar 

  17. Jin, H., Xie, Z., George, S. R., and O'Dowd, B. F. (1999) Palmitoylation occurs at cysteine 347 and cysteine 351 of the dopamine D(1) receptor. Eur. J. Pharmacol. 386, 305–312.

    Article  CAS  PubMed  Google Scholar 

  18. Unger, V. M., Hargrave, P. A., Baldwin, J. M., and Schertler, G. F. (1997) Arrangement of rhodopsin transmembrane alpha-helices. Nature. 389, 203–206.

    Article  CAS  PubMed  Google Scholar 

  19. Palczewski, K., Kumasaka, T., Hori, T., et al. (2000) Crystal structure of rhodopsin: a G pro-tein-coupled receptor. Science. 289, 739–745.

    Article  CAS  PubMed  Google Scholar 

  20. Dohlman, H. G., Thorner, J., Caron, M. G., and Lefkowitz, R. J. (1991) Model systems for the study of seven-transmembrane-segment receptors. Annu. Rev. Biochem. 60, 653–688.

    Article  CAS  PubMed  Google Scholar 

  21. Hibert, M. F., Trumpp-Kallmeyer, S., Hoflack, J., and Bruinvels, A. (1993) This is not a G protein-coupled receptor. Trends Pharmacol. Sci. 14, 7–12.

    Article  CAS  PubMed  Google Scholar 

  22. Strader, C. D., Fong, T. M., Tota, M. R., Underwood, D., and Dixon, R. A. (1994) Structure and function of G protein-coupled receptors. Annu. Rev. Biochem. 63, 101–132.

    Article  CAS  PubMed  Google Scholar 

  23. Rana, B. K., Shiina, T., and Insel, P. A. (2001) Genetic variations and polymorphisms of G protein-coupled receptors: Functional and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 41, 593–624.

    Article  CAS  PubMed  Google Scholar 

  24. Sadee, W., Hoeg, E., Lucas, J., and Wang, D. X. (2001) Genetic variations in human G protein-coupled receptors: implications for drug therapy. AAPS Pharmsci. 3.

    Google Scholar 

  25. Neves, S. R., and Iyengar, R. (2002) Modeling of signaling networks. Bioessays. 24, 1110–1117.

    Article  CAS  PubMed  Google Scholar 

  26. Lynch, K. R., O'Neill, G. P., Liu, Q. Y., et al. (1999) Characterization of the human cysteinyl leukotriene CysLT(1) receptor. Nature. 399, 789–793.

    Article  CAS  PubMed  Google Scholar 

  27. Heise, C. E., O'Dowd, B. F., Figueroa, D. J., et al. (2000) Characterization of the human cysteinyl leukotriene 2 receptor. J. Biol. Chem. 275, 30531–30536.

    Article  CAS  PubMed  Google Scholar 

  28. Figueroa, D. J., Breyer, R. M., Defoe, S. K., et al. (2001) Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am. J. Resp. Crit. Care Med. 163, 226–233.

    CAS  PubMed  Google Scholar 

  29. Mellor, E. A., Frank, N., Soler, D., et al.. (2003) Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: functional distinction from CysLT1R. Proc. Natl. Acad. Sci. U. S. Am. 100, 11589–11593.

    Article  CAS  Google Scholar 

  30. Sjostrom, M., Johansson, A. S., Schroder, O., Qiu, H., Palmblad, J., and Haeggstrom, J. Z. (2003) Dominant expression of the CysLT(2) receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endothelial cells. Arterioscler. Thromb. Vasc. Biol. 23, E37–E41.

    Article  PubMed  CAS  Google Scholar 

  31. Milligan, G. (2004) G protein-coupled receptor dimerization: function and ligand pharmacology. Mol. Pharmacol. 66, 1–7.

    Article  CAS  PubMed  Google Scholar 

  32. Gomes, I., Jordan, B. A., Gupta, A., Rios, C., Trapaidze, N., and Devi, L. A. (2001) G protein coupled receptor dimerization: implications in modulating receptor function. J. Mol. Med. 79, 226–242.

    Article  CAS  PubMed  Google Scholar 

  33. AbdAlla, S., Lother, H., and Quitterer, U. (2000) AT(1)-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature. 407, 94–98.

    Article  CAS  PubMed  Google Scholar 

  34. AbdAlla, S., Lother, H., Langer, A., el Faramawy, Y., and Quitterer, U. (2004) Factor XIIIA transglutaminase crosslinks AT(1) receptor dimers of monocytes at the onset of atherosclerosis. Cell. 119, 343–354.

    Article  CAS  PubMed  Google Scholar 

  35. Zeng, F. Y., and Wess, J. (1999) Identification and molecular characterization of m3 muscarinic receptor dimers. J. Biol. Chem. 274, 19487–19497.

    Article  CAS  PubMed  Google Scholar 

  36. George, S. R., Lee, S. P., Varghese, G., et al. (1998) A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization. J. Biol. Chem. 273, 30244–30248.

    Article  CAS  PubMed  Google Scholar 

  37. Lee, S. P., O'Dowd, B. F., Rajaram, R. D., Nguyen, T., and George, S. R. (2003) D2 dopamine receptor homodimerization is mediated by multiple sites of interaction, including an intermolecular interaction involving transmembrane domain 4. Biochemistry. 42, 11023–11031.

    Article  CAS  PubMed  Google Scholar 

  38. Romano, C., Yang, W. L., and KL, O. M. (1996) Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J. Biol. Chem. 271, 28612–28616.

    Article  CAS  PubMed  Google Scholar 

  39. Karnik, S. S., Sakmar, T. P., Chen, H. B., and Khorana, H. G. (1988) Cysteine residues 110 and 187 are essential for the formation of correct structure in bovine rhodopsin. Proc. Natl. Acad. Sci. U. S. A. 85, 8459–8463.

    Article  CAS  PubMed  Google Scholar 

  40. Savarese, T. M., Wang, C. D., and Fraser, C. M. (1992) Site-directed mutagenesis of the rat m1 muscarinic acetylcholine receptor. Role of conserved cysteines in receptor function. J. Biol. Chem. 267, 11439–11448.

    CAS  PubMed  Google Scholar 

  41. Zhang, P., Johnson, P. S., Zollner, C., et al. (1999) Mutation of human mu opioid receptor extracellular “disulfide cysteine” residues alters ligand binding but does not prevent receptor targeting to the cell plasma membrane. Brain Res. Mol. Brain Res. 72, 195–204.

    Article  CAS  PubMed  Google Scholar 

  42. Capra, V., Thompson, M. D., Cole, D. E. C., Sala, A., Folco, G., and Rovati, G. E. (2007) Cysteinyl-leukotrienes and their receptors in health and disease. Med. Res. Rev. 27, 469–527.

    Article  CAS  PubMed  Google Scholar 

  43. Thompson, M. D., Burnham, W. M., and Cole, D. E. C. (2005) The G protein-coupled receptors: pharmacogenetics and disease. Crit. Rev. Clin. Lab. Sci. 42, 311–392.

    Article  CAS  PubMed  Google Scholar 

  44. Gainetdinov, R. R., Premont, R. T., Bohn, L. M., Lefkowitz, R. J., and Caron, M. G. (2004) Desensitization of G protein-coupled receptors and neuronal functions. Annu. Rev. Neurosci. 27, 107–144.

    Article  CAS  PubMed  Google Scholar 

  45. Lefkowitz, R. J. (2004) Historical review: a brief history and personal retrospective of seven-transmembrane receptors. Trends Pharmacol. Sci. 25, 413–422.

    Article  CAS  PubMed  Google Scholar 

  46. Spiegel, A. M., and Weinstein, L. S. (2004) Inherited diseases involving G proteins and G protein-coupled receptors. Annu. Rev. Med. 55, 27–39.

    Article  CAS  PubMed  Google Scholar 

  47. Wensel, T. (1999) Introduction to cellular signal transduction. (Sitaramayya, A. ed.) Heterotrimeric G-Proteins: Structure, regulation and signaling mechanisms. Introductory Signal Transduction pp. 29–46. Birkhanser, Boston, MA.

    Google Scholar 

  48. Spiegel, A. M. (1996) Defects in G protein-coupled signal transduction in human disease. Annu. Rev. Physiol. 58, 143–70.

    Article  CAS  PubMed  Google Scholar 

  49. Sunahara, R. K., Dessauer, C. W., and Gilman, A. G. (1996) Complexity and diversity of mammalian adenylyl cyclases. Annu. Rev. Pharmacol. Toxicol. 36, 461–480.

    Article  CAS  PubMed  Google Scholar 

  50. Tang, C. M., and Insel, P. A. (2005) Genetic variation in G-protein-coupled receptors–consequences for G-protein-coupled receptors as drug targets. Expert. Opin. Ther. Targets. 9, 1247–1265.

    Article  CAS  PubMed  Google Scholar 

  51. Rebois, R. V., and Hebert, T. E. (2003) Protein complexes involved in heptahelical receptor-mediated signal transduction. Receptors Channels. 9, 169–194.

    Article  CAS  PubMed  Google Scholar 

  52. Logothetis, D. E., Kurachi, Y., Galper, J., Neer, E. J., and Clapham, D. E. (1987) The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature. 325, 321–326.

    Article  CAS  PubMed  Google Scholar 

  53. Premont, R. T., Inglese, J., and Lefkowitz, R. J. (1995) Protein kinases that phosphorylate activated G protein-coupled receptors. FASEB J. 9, 175–82.

    CAS  PubMed  Google Scholar 

  54. Ray, K., Kunsch, C., Bonner, L. M., and Robishaw, J. D. (1995) Isolation of cDNA clones encoding eight different human G protein gamma subunits, including three novel forms designated the gamma 4, gamma 10, and gamma 11 subunits. J. Biol. Chem. 270, 21765–21771.

    Article  CAS  PubMed  Google Scholar 

  55. Hepler, J. R., and Gilman, A. G. (1992) G-proteins. Trends Biochem. Sci. 17, 383–387.

    Article  CAS  PubMed  Google Scholar 

  56. Siffert, W., Rosskopf, D., Siffert, G., et al. (1998) Association of a human G-protein beta3 subunit variant with hypertension. Nat. Genet. 18, 45–48.

    Article  CAS  PubMed  Google Scholar 

  57. Sun, A., Ge, J., Siffert, W., and Frey, U. H. (2005) Quantification of allele-specific G-protein beta3 subunit mRNA transcripts in different human cells and tissues by Pyrosequencing. Eur. J. Hum. Genet. 13, 361–369.

    Article  CAS  PubMed  Google Scholar 

  58. Siffert, W. (2001) Molecular genetics of G proteins and atherosclerosis risk. Basic Res. Cardiol. 96, 606–611.

    Article  CAS  PubMed  Google Scholar 

  59. Mitchell, A., Pace, M., Nurnberger, J., et al. (2005) Insulin-mediated venodilation is impaired in young, healthy carriers of the 825T allele of the G-protein beta3 subunit gene (GNB3). Clin. Pharmacol. Ther. 77, 495–502.

    Article  CAS  PubMed  Google Scholar 

  60. Matsunaga, T., Nagasumi, K., Yamamura, T., et al. (2005) Association of C825T polymorphism of G protein beta3 subunit with the autonomic nervous system in young healthy Japanese individuals. Am. J. Hypertens. 18, 523–529.

    Article  CAS  PubMed  Google Scholar 

  61. Kiani, J. G., Saeed, M., Parvez, S. H., and Frossard, P. M. (2005) Association of G-protein beta-3 subunit gene (GNB3) T825 allele with type II diabetes. Neuro. Endocrinol. Lett. 26, 87–88.

    CAS  PubMed  Google Scholar 

  62. Fernandez-Real, J. M., Penarroja, G., Richart, C., et al. (2003) G protein beta3 gene variant, vascular function, and insulin sensitivity in type 2 diabetes. Hypertension. 41, 124–129.

    Article  CAS  PubMed  Google Scholar 

  63. Terra, S. G., McGorray, S. P., Wu, R., et al. (2005) Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study. Int. J Obes. (Lond). 29, 746–754.

    Article  CAS  Google Scholar 

  64. Andersen, G., Overgaard, J., Albrechtsen, A., et al. (2006) Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes. Diabetologia. 49, 75–82.

    Article  CAS  PubMed  Google Scholar 

  65. Meirhaeghe, A., Cottel, D., Amouyel, P., and Dallongeville, J. (2005) Lack of association between certain candidate gene polymorphisms and the metabolic syndrome. Mol. Genet. Metab. 86, 293–299.

    Article  CAS  PubMed  Google Scholar 

  66. Bullido, M. J., Ramos, M. C., Ruiz-Gomez, A., et al. (2004) Polymorphism in genes involved in adrenergic signaling associated with Alzheimer's. Neurobiol. Aging. 25, 853–859.

    Article  CAS  PubMed  Google Scholar 

  67. Klintschar, M., Stiller, D., Schwaiger, P., and Kleiber, M. (2005) DNA polymorphisms in the tyrosine hydroxylase and GNB3 genes: association with unexpected death from acute myocardial infarction and increased heart weight. Forensic Sci. Int. 153, 142–146.

    Article  CAS  PubMed  Google Scholar 

  68. Eisenhardt, A., Siffert, W., Rosskopf, D., et al. (2005) Association study of the G-protein beta3 subunit C825T polymorphism with disease progression in patients with bladder cancer. World J. Urol. 23, 279–286.

    Article  CAS  PubMed  Google Scholar 

  69. Sheu, S. Y., Gorges, R., Ensinger, C., et al. (2005) Different genotype distribution of the GNB3 C825T polymorphism of the G protein beta3 subunit in adenomas and differentiated thyroid carcinomas of follicular cell origin. J. Pathol. 207, 430–435.

    Article  CAS  PubMed  Google Scholar 

  70. Sarrazin, C., Berg, T., Weich, V., et al. (2005) GNB3 C825T polymorphism and response to interferon-alfa/ribavirin treatment in patients with hepatitis C virus genotype 1 (HCV-1) infection. J. Hepatol. 43, 388–393.

    Article  CAS  PubMed  Google Scholar 

  71. Lee, H. J., Cha, J. H., Ham, B. J., et al. (2004) Association between a G-protein beta 3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Pharmacogenomics. J. 4, 29–33.

    Article  CAS  PubMed  Google Scholar 

  72. Muller, D. J., De, L., V, Sicard, T., et al. (2005) Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia. Eur. Neuropsychopharmacol. 15, 525–531.

    Article  PubMed  CAS  Google Scholar 

  73. Schelleman, H., Stricker, B. H., Verschuren, W. M., et al. (2006) Interactions between five candidate genes and antihypertensive drug therapy on blood pressure. Pharmacogenomics. J. 6, 22–26.

    Article  CAS  PubMed  Google Scholar 

  74. Muller, S., and Lohse, M. J. (1995) The role of G-protein beta gamma subunits in signal transduction. Biochem. Soc. Trans. 23, 141–148.

    CAS  PubMed  Google Scholar 

  75. Tang, W. J., and Gilman, A. G. (1991) Type-specific regulation of adenylyl cyclase by G protein beta gamma subunits. Science. 254, 1500–1503.

    Article  CAS  PubMed  Google Scholar 

  76. Ueda, N., Iniguez-Lluhi, J. A., Lee, E., Smrcka, A. V., Robishaw, J. D., and Gilman, A. G. (1994) G protein beta gamma subunits. Simplified purification and properties of novel isoforms. J. Biol. Chem. 269, 4388–4395.

    CAS  PubMed  Google Scholar 

  77. Boyer, J. L., Graber, S. G., Waldo, G. L., Harden, T. K., and Garrison, J. C. (1994) Selective activation of phospholipase C by recombinant G-protein alpha- and beta gamma-subunits. J. Biol. Chem. 269, 2814–2819.

    CAS  PubMed  Google Scholar 

  78. Carty, D. J., Padrell, E., Codina, J., Birnbaumer, L., Hildebrandt, J. D., and Iyengar, R. (1990) Distinct guanine nucleotide binding and release properties of the three Gi proteins. J. Biol. Chem. 265, 6268–6273.

    CAS  PubMed  Google Scholar 

  79. Bourne, H. R., and Stryer, L. (1992) G proteins. The target sets the tempo [news]. Nature. 358, 541–543.

    Article  CAS  PubMed  Google Scholar 

  80. Tanabe, S., Kreutz, B., Suzuki, N., and Kozasa, T. (2004) Regulation of RGS-RhoGEFs by G alpha 12 and G alpha 13 proteins. Reg. G-Protein Signal. B. 390, 285–294.

    Article  CAS  Google Scholar 

  81. Weinstein, L. S., Chen, M., Xie, T., and Liu, J. (2006) Genetic diseases associated with heterotrimeric G proteins. Trends Pharmacol. Sci. 27, 260–266.

    Article  CAS  PubMed  Google Scholar 

  82. Gejman, P. V., Weinstein, L. S., Martinez, M., et al. (1991) Genetic mapping of the Gs-alpha subunit gene (GNAS1) to the distal long arm of chromosome 20 using a polymorphism detected by denaturing gradient gel electrophoresis. Genomics. 9, 782–783.

    Article  CAS  PubMed  Google Scholar 

  83. Shenker, A., Weinstein, L. S., Sweet, D. E., and Spiegel, A. M. (1994) An activating Gs alpha mutation is present in fibrous dysplasia of bone in the McCune-Albright syndrome. J. Clin. Endocrinol. Metab. 79, 750–755.

    Article  CAS  PubMed  Google Scholar 

  84. Fragoso, M. C., Domenice, S., Latronico, A. C., et al. (2003) Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J. Clin. Endocrinol. Metab. 88, 2147–2151.

    Article  CAS  PubMed  Google Scholar 

  85. Roman, R., Johnson, M. C., Codner, E., Boric, M. A., Avila, A., and Cassorla, F. (2004) Activating GNAS1 gene mutations in patients with premature thelarche. J. Pediatr. 145, 218–222.

    Article  CAS  PubMed  Google Scholar 

  86. Spiegel, A. M. (1990) Albright's hereditary osteodystrophy and defective G proteins. N. Engl. J Med. 322, 1461–1462.

    Article  CAS  PubMed  Google Scholar 

  87. Weinstein, L. S., Yu, S., Warner, D. R., and Liu, J. (2001) Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr. Rev. 22, 675–705.

    Article  CAS  PubMed  Google Scholar 

  88. Bastepe, M., Weinstein, L. S., Ogata, N., et al. (2004) Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc. Natl. Acad. Sci. U. S. A. 101, 14794–14799.

    Article  CAS  PubMed  Google Scholar 

  89. Sakamoto, A., Chen, M., Kobayashi, T., Kronenberg, H. M., and Weinstein, L. S. (2005) Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J. Bone Miner. Res. 20, 663–671.

    Article  CAS  PubMed  Google Scholar 

  90. Germain-Lee, E. L., Groman, J., Crane, J. L., Jan de Beur, S. M., and Levine, M. A. (2003) Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J. Clin. Endocrinol. Metab. 88, 4059–4069.

    Article  CAS  PubMed  Google Scholar 

  91. Mantovani, G., Maghnie, M., Weber, G., et al. (2003) Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gs alpha gene. J. Clin. Endocrinol. Metab. 88, 4070–4074.

    Article  CAS  PubMed  Google Scholar 

  92. Yu, S., Yu, D., Lee, E., Eckhaus, M., et al. (1998) Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. Proc. Natl. Acad. Sci. U. S. A. 95, 8715–8720.

    Article  CAS  PubMed  Google Scholar 

  93. Hayward, B. E., Barlier, A., Korbonits, M., et al. (2001) Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J. Clin. Invest. 107, R31–R36.

    Article  CAS  PubMed  Google Scholar 

  94. Mantovani, G., Ballare, E., Giammona, E., Beck-Peccoz, P., and Spada, A. (2002) The gsalpha gene: predominant maternal origin of transcription in human thyroid gland and gonads. J. Clin. Endocrinol. Metab. 87, 4736–4740.

    Article  CAS  PubMed  Google Scholar 

  95. Germain-Lee, E. L., Ding, C. L., Deng, Z., et al. (2002) Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem. Biophys. Res. Commun. 296, 67–72.

    Article  CAS  PubMed  Google Scholar 

  96. Liu, J., Erlichman, B., and Weinstein, L. S. (2003) The stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J. Clin. Endocrinol. Metab. 88, 4336–4341.

    Article  CAS  PubMed  Google Scholar 

  97. Bastepe, M., Frohlich, L. F., Linglart, A., et al. (2005) Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat. Genet 37, 25–27.

    Article  CAS  PubMed  Google Scholar 

  98. Bastepe, M., Lane, A. H., and Juppner, H. (2001) Paternal uniparental isodisomy of chromosome 20q–and the resulting changes in GNAS1 methylation–as a plausible cause of pseudohypoparathyroidism. Am. J. Hum. Genet 68, 1283–1289.

    Article  CAS  PubMed  Google Scholar 

  99. Wu, W. I., Schwindinger, W. F., Aparicio, L. F., and Levine, M. A. (2001) Selective resistance to parathyroid hormone caused by a novel uncoupling mutation in the carboxyl terminus of G alpha(s). A cause of pseudohypoparathyroidism type Ib. J. Biol. Chem. 276, 165–171.

    Article  CAS  PubMed  Google Scholar 

  100. Cismowski, M. J. (2006) Non-receptor activators of heterotrimeric G-protein signaling (AGS proteins). Semin. Cell Dev. Biol. 17, 334–344.

    Article  CAS  PubMed  Google Scholar 

  101. Sato, M., Cismowski, M. J., Toyota, E., et al. (2006) Identification of a receptor-independent activator of G protein signaling (AGS8) in ischemic heart and its interaction with Gbetagamma. Proc. Natl. Acad. Sci. U. S. A. 103, 797–802.

    Article  CAS  PubMed  Google Scholar 

  102. Hall, R. A., and Lefkowitz, R. J. (2002) Regulation of G protein-coupled receptor signaling by scaffold proteins. Circ. Res. 91, 672–680.

    Article  CAS  PubMed  Google Scholar 

  103. 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, 235–271.

    Article  PubMed  Google Scholar 

  104. Hepler, J. R. (2003) RGS protein and G protein interactions: A little help from their friends. Mol. Pharmacol. 64, 547–549.

    Article  CAS  PubMed  Google Scholar 

  105. Roy, A. A., Lemberg, K. E., and Chidiac, P. (2003) Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions. Mol. Pharmacol. 64, 587–593.

    Article  CAS  PubMed  Google Scholar 

  106. Cismowski, M. J. (2006) Non-receptor activators of heterotrimeric G-protein signaling (AGS proteins). Semin. Cell Dev. Biol. 17, 334–344.

    Article  CAS  PubMed  Google Scholar 

  107. Sato, M., Cismowski, M. J., Toyota, E., et al. (2006) Identification of a receptor-independent activator of G protein signaling (AGS8) in ischemic heart and its interaction with Gbetagamma. Proc. Natl. Acad. Sci. U. S. A. 103, 797–802.

    Article  CAS  PubMed  Google Scholar 

  108. Cismowski, M. J. (2006) Non-receptor activators of heterotrimeric G-protein signaling (AGS proteins). Semin. Cell Dev. Biol. 17, 334–344.

    Article  CAS  PubMed  Google Scholar 

  109. Sato, M., Cismowski, M. J., Toyota, E., et al. (2006) Identification of a receptor-independent activator of G protein signaling (AGS8) in ischemic heart and its interaction with Gbetagamma. Proc. Natl. Acad. Sci. U. S. A. 103, 797–802.

    Article  CAS  PubMed  Google Scholar 

  110. Riddle, E. L., Rana, B. K., Murthy, K. K., Rao, F., Eskin, E., O'Connor, D. T., and Insel, P. A. (2006) Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. Hypertension. 47, 415–420.

    Article  CAS  PubMed  Google Scholar 

  111. Chidiac, P., and Roy, A. A. (2003) Activity, regulation, and intracellular localization of RGS proteins. Receptors Channels. 9, 135–147.

    Article  CAS  PubMed  Google Scholar 

  112. Bernstein, L. S., Ramineni, S., Hague, C., et al. (2004) RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate G(q/11 alpha) signaling. J. Biol. Chem. 279, 21248–21256.

    Article  CAS  PubMed  Google Scholar 

  113. Heximer, S. P., Knutsen, R. H., Sun, X., et al. (2003) Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J. Clin. Invest. 111, 1259.

    Article  CAS  PubMed  Google Scholar 

  114. Sun, X., Kaltenbronn, K. M., Steinberg, T. H., and Blumer, K. J. (2005) RGS2 is a mediator of nitric oxide action on blood pressure and vasoconstrictor signaling. Mol. Pharmacol. 67, 631–639.

    Article  CAS  PubMed  Google Scholar 

  115. Tiret, L., Bonnardeaux, A., Poirier, O., et al. (1994) Synergistic effects of angiotensin-con-verting enzyme and angiotensin-II type-1 receptor gene polymorphisms on risk of myocar-dial-infarction. Lancet. 344, 910–913.

    Article  CAS  PubMed  Google Scholar 

  116. Takami, S., Katsuya, T., Rakugi, H., et al. (1998) Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension. Am. J. Hypertens. 11, 316–321.

    Article  CAS  PubMed  Google Scholar 

  117. Calo, L. A., Pagnin, E., Davis, P. A., et al. (2004) Increased expression of regulator of G protein signaling-2 (RGS-2) in Bartter's/Gitelman's syndrome. A role in the control of vascular tone and implication for hypertension. J. Clin. Endocrinol. Metab. 89, 4153–4157.

    Article  CAS  PubMed  Google Scholar 

  118. Gao, Y., Portugal, A. D., Negash, S., Zhou, W., Longo, L. D., and Raj, J. U. (2007) Role of Rho kinases in PKG-mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia. Am. J. Physiol Lung Cell. Mol. Physiol. 292, L678–L684.

    Article  CAS  PubMed  Google Scholar 

  119. Riddle, E. L., Schwartzman, R. A., Bond, M., and Insel, P. A. (2005) Multi-tasking RGS proteins in the heart: the next therapeutic target? Circ. Res. 96, 401–411.

    Article  CAS  PubMed  Google Scholar 

  120. Semplicini, A., Lenzini, L., Sartori, M., et al. (2006) Reduced expression of regulator of G-protein signaling 2 (RGS2) in hypertensive patients increases calcium mobilization and ERK1/2 phosphorylation induced by angiotensin II. J. Hypertens. 24, 1115–1124.

    Article  CAS  PubMed  Google Scholar 

  121. Salomon, Y., Londos, C., and Rodbell, M. (1974) A highly sensitive adenylate cyclase assay. Anal. Biochem. 58, 541–548.

    Article  CAS  PubMed  Google Scholar 

  122. Lamey, M., Thompson, M., Varghese, G., et al. (2002) Distinct residues in the carboxyl tail mediate agonist-induced desensitization and internalization of the human dopamine D-1 receptor. J. Biol. Chem. 277, 9415–9421.

    Article  CAS  PubMed  Google Scholar 

  123. Krupnick, J. G., and Benovic, J. L. (1998) The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Annu. Rev. Pharmacol. Toxicol. 38, 289–319.

    Article  CAS  PubMed  Google Scholar 

  124. Zhao, X., Palczewski, K., and Ohguro, H. (1995) Mechanism of rhodopsin phosphorylation. Biophys. Chem. 56, 183–188.

    Article  CAS  PubMed  Google Scholar 

  125. Jiang, D., and Sibley, D. R. (1999) Regulation of D(1) dopamine receptors with mutations of protein kinase phosphorylation sites: attenuation of the rate of agonist-induced desensitization. Mol. Pharmacol. 56, 675–683.

    CAS  PubMed  Google Scholar 

  126. Hausdorff, W. P., Bouvier, M., O'Dowd, B. F., Irons, G. P., Caron, M. G., and Lefkowitz, R. J. (1989) Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization. J. Biol. Chem. 264, 12657–12665.

    CAS  PubMed  Google Scholar 

  127. Lohse, M. J., Benovic, J. L., Caron, M. G., and Lefkowitz, R. J. (1990) Multiple pathways of rapid beta 2-adrenergic receptor desensitization. Delineation with specific inhibitors. J. Biol. Chem. 265, 3202–3211.

    CAS  PubMed  Google Scholar 

  128. Lohse, M. J. (1993) Molecular mechanisms of membrane receptor desensitization. Biochim. Biophys. Acta. 1179, 171–188.

    Article  CAS  PubMed  Google Scholar 

  129. Lewis, M. M., Watts, V. J., Lawler, C. P., Nichols, D. E., and Mailman, R. B. (1998) Homologous desensitization of the D1A dopamine receptor: efficacy in causing desensitization dissociates from both receptor occupancy and functional potency. J. Pharmacol. Exp. Ther. 286, 345–353.

    CAS  PubMed  Google Scholar 

  130. Shih, M., and Malbon, C. C. (1994) Oligodeoxynucleotides antisense to mRNA encoding protein kinase A, protein kinase C, and beta-adrenergic receptor kinase reveal distinctive cell-type-specific roles in agonist-induced desensitization. Proc. Natl. Acad. Sci. U. S. A. 91, 12193–12197.

    Article  CAS  PubMed  Google Scholar 

  131. Roth, N. S., Campbell, P. T., Caron, M. G., Lefkowitz, R. J., and Lohse, M. J. (1991) Comparative rates of desensitization of beta-adrenergic receptors by the beta-adrenergic receptor kinase and the cyclic AMP-dependent protein kinase. Proc. Natl. Acad. Sci. U. S. A. 88, 6201–6204.

    Article  CAS  PubMed  Google Scholar 

  132. Eason, M. G., Moreira, S. P., and Liggett, S. B. (1995) Four consecutive serines in the third intracellular loop are the sites for beta-adrenergic receptor kinase-mediated phosphorylation and desensitization of the alpha 2A-adrenergic receptor. J. Biol. Chem. 270, 4681–4688.

    Article  CAS  PubMed  Google Scholar 

  133. Diviani, D., Lattion, A. L., and Cotecchia, S. (1997) Characterization of the phosphorylation sites involved in G protein- coupled receptor kinase- and protein kinase C-mediated desensitization of the alpha1B-adrenergic receptor. J. Biol. Chem. 272, 28712–28719.

    Article  CAS  PubMed  Google Scholar 

  134. Maestes, D. C., Potter, R. M., and Prossnitz, E. R. (1999) Differential phosphorylation paradigms dictate desensitization and internalization of the N-formyl peptide receptor. J. Biol. Chem. 274, 29791–29795.

    Article  CAS  PubMed  Google Scholar 

  135. Tsuga, H., Kameyama, K., Haga, T., Honma, T., Lameh, J., and Sadee, W. (1998) Internalization and down-regulation of human muscarinic acetylcholine receptor m2 subtypes. Role of third intracellular m2 loop and G protein- coupled receptor kinase 2. J. Biol. Chem. 273, 5323–5330.

    Article  CAS  PubMed  Google Scholar 

  136. Pals-Rylaarsdam, R., and Hosey, M. M. (1997) Two homologous phosphorylation domains differentially contribute to desensitization and internalization of the m2 muscarinic acetylcholine receptor. J. Biol. Chem. 272, 14152–14158.

    Article  CAS  PubMed  Google Scholar 

  137. Tiberi, M., Nash, S. R., Bertrand, L., Lefkowitz, R. J., and Caron, M. G. (1996) Differential regulation of dopamine D1A receptor responsiveness by various G protein-coupled receptor kinases. J. Biol. Chem. 271, 3771–3778.

    Article  CAS  PubMed  Google Scholar 

  138. Bouvier, M., Hausdorff, W. P., de Blasi, A., et al. (1988) Removal of phosphorylation sites from the beta 2-adrenergic receptor delays onset of agonist-promoted desensitization. Nature. 333, 370–373.

    Article  CAS  PubMed  Google Scholar 

  139. Hausdorff, W. P., Campbell, P. T., Ostrowski, J., Yu, S. S., Caron, M. G., and Lefkowitz, R. J. (1991) A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation. Proc. Natl. Acad. Sci. U. S. A. 88, 2979–2983.

    Article  CAS  PubMed  Google Scholar 

  140. Fredericks, Z. L., Pitcher, J. A., and Lefkowitz, R. J. (1996) Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor. J. Biol. Chem. 271, 13796–13803.

    Article  CAS  PubMed  Google Scholar 

  141. Seibold, A., January, B. G., Friedman, J., Hipkin, R. W., and Clark, R. B. (1998) Desensitization of beta2-adrenergic receptors with mutations of the proposed G protein-cou-pled receptor kinase phosphorylation sites. J. Biol. Chem. 273, 7637–7642.

    Article  CAS  PubMed  Google Scholar 

  142. Pak, Y., O'Dowd, B. F., and George, S. R. (1997) Agonist-induced desensitization of the mu opioid receptor is determined by threonine 394 preceded by acidic amino acids in the COOH-terminal tail. J. Biol. Chem. 272, 24961–24965.

    Article  CAS  PubMed  Google Scholar 

  143. Guo, J., Wu, Y., Zhang, W., Zhao, J., Devi, L. A., Pei, G., and Ma, L. (2000) Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimu-lated delta-opioid receptor phosphorylation. Mol. Pharmacol. 58, 1050–1056.

    CAS  PubMed  Google Scholar 

  144. Palmer, T. M., Benovic, J. L., and Stiles, G. L. (1995) Agonist-dependent phosphorylation and desensitization of the rat A3 adenosine receptor. Evidence for a G-protein-coupled receptor kinase- mediated mechanism. J. Biol. Chem. 270, 29607–29613.

    Article  CAS  PubMed  Google Scholar 

  145. Palmer, T. M., Stiles, G. L. (1997) Identification of an A2a adenosine receptor domain specifically responsible for mediating short-term desensitization. Biochemistry. 36, 832–838.

    Article  CAS  PubMed  Google Scholar 

  146. Palmer, T. M., Stiles, G. L. (2000) Identification of threonine residues controlling the agonist-dependent phosphorylation and desensitization of the rat A(3) adenosine receptor [in process citation]. Mol Pharmacol 57, 539–545.

    CAS  PubMed  Google Scholar 

  147. Vargas, G. A., von Zastrow, M. (2004) Identification of a novel endocytic recycling signal in the D1 dopamine receptor. J. Biol. Chem. 279, 37461–37469.

    Article  CAS  PubMed  Google Scholar 

  148. Ohguro, H., Van Hooser, J. P., Milam, A. H., and Palczewski, K. (1995) Rhodopsin phosphorylation and dephosphorylation in vivo. J. Biol. Chem. 270, 14259–14262.

    Article  CAS  PubMed  Google Scholar 

  149. Thompson, M. D., Burnham, W. M., and Cole, D. E. (2005) The G protein-coupled receptors: pharmacogenetics and disease. Crit Rev. Clin Lab Sci. 42, 311–392.

    Article  CAS  PubMed  Google Scholar 

  150. Kim, O. J., Gardner, B. R., Williams, D. B., et al. (2004) The role of phosphorylation in D1 dopamine receptor desensitization: evidence for a novel mechanism of arrestin association. J Biol. Chem. 279, 7999–8010.

    Article  CAS  PubMed  Google Scholar 

  151. Ferguson, S. S., Barak, L. S., Zhang, J., and Caron, M. G. (1996) G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins. Can. J. Physiol. Pharmacol. 74, 1095–1110.

    Article  CAS  PubMed  Google Scholar 

  152. Ferguson, S. S., Downey, W. E. 3., 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, 363–366.

    Article  CAS  PubMed  Google Scholar 

  153. Faussner, A., Proud, D., Towns, M., and Bathon, J. M. (1998) Influence of the cytosolic carboxyl termini of human B1 and B2 kinin receptors on receptor sequestration, ligand internalization, and signal transduction. J. Biol. Chem. 273, 2617–2623.

    Article  CAS  PubMed  Google Scholar 

  154. Tan, C. M., Brady, A. E., Nickols, H. H., Wang, Q., and Limbird, L. E. (2004) Membrane trafficking of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 44, 559–609.

    Article  CAS  PubMed  Google Scholar 

  155. Pals-Rylaarsdam, R., Xu, Y., Witt-Enderby, P., Benovic, J. L., and Hosey, M. M. (1995) Desensitization and internalization of the m2 muscarinic acetylcholine receptor are directed by independent mechanisms. J. Biol. Chem. 270, 29004–29011.

    Article  CAS  PubMed  Google Scholar 

  156. Seibold, A., Williams, B., Huang, Z. F., et al. (2000) Localization of the sites mediating desensitization of the beta(2)-adrenergic receptor by the GRK pathway. Mol. Pharmacol. 58, 1162–1173.

    CAS  PubMed  Google Scholar 

  157. Pak, Y., O'Dowd, B. F., Wang, J. B., and George, S. R. (1999) Agonist-induced, G protein-dependent and -independent down-regulation of the mu opioid receptor. The receptor is a direct substrate for protein-tyrosine kinase. J. Biol. Chem. 274, 27610–27616.

    Article  CAS  PubMed  Google Scholar 

  158. Hasbi, A., Allouche, S., Sichel, F., et al. (2000) Internalization and recycling of delta-opioid receptor are dependent on a phosphorylation-dephosphorylation mechanism. J. Biol. Chem. 293, 237–247.

    CAS  Google Scholar 

  159. Mathuru, A. L., Mundell, S. L., Benovic, J. L., and Kelly, E. (2001) Rapid agonist-induced desensitization and internalization of the a2b adenosine receptor is mediated by a serine residue close to the COOH terminus. J. Biochem. 276, 30199–30207.

    Google Scholar 

  160. Holtmann, M. H., Roettger, B. F., Pinon, D. I., and Miller, L. J. (1996) Role of receptor phosphorylation in desensitization and internalization of the secretin receptor. J. Biol. Chem. 271, 23566–23571.

    Article  CAS  PubMed  Google Scholar 

  161. Moffett, S., Rousseau, G., Lagace, M., and Bouvier, M. (2001) The palmitoylation state of the beta2-adrenergic receptor regulates the synergistic action of cyclic AMP-dependent protein kinase and beta2-adrenergic receptor kinase involved in its phosphorylation and desensitization. J. Neurochem. 76, 269–279.

    Article  CAS  PubMed  Google Scholar 

  162. Lee, K. B., Ptasienski, J. A., Pals-Rylaarsdam, R., Gurevich, V. V., and Hosey, M. M. (2000) Arrestin binding to the M(2) muscarinic acetylcholine receptor is precluded by an inhibitory element in the third intracellular loop of the receptor. J. Biol. Chem. 275, 9284–9289.

    Article  CAS  PubMed  Google Scholar 

  163. Goodman, O. B., Jr., Krupnick, J. G., Santini, F., et al. (1996) Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2- adrenergic receptor. Nature. 383, 447–450.

    Article  CAS  PubMed  Google Scholar 

  164. Hinshaw, J. E., and Schmid, S. L. (1995) Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding [see comments]. Nature. 374, 190–192.

    Article  CAS  PubMed  Google Scholar 

  165. Takei, K., McPherson, P. S., Schmid, S. L., and De Camilli, P. (1995) Tubular membrane invaginations coated by dynamin rings are induced by GTP-gamma S in nerve terminals [see comments]. Nature. 374, 186–190.

    Article  CAS  PubMed  Google Scholar 

  166. Schmid, S. L. (1992) The mechanism of receptor-mediated endocytosis–more questions than answers. Bioessays. 14, 589–596.

    Article  CAS  PubMed  Google Scholar 

  167. Lefkowitz, R. J. (1998) G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling and desensitization. J. Biol. Chem. 273, 18677–18680.

    Article  CAS  PubMed  Google Scholar 

  168. Freedman, N. J., and Lefkowitz, R. J. (1996) Desensitization of G protein-coupled receptors. Recent Prog. Horm. Res. 51, 319–351.

    CAS  PubMed  Google Scholar 

  169. Pitcher, J. A., Freedman, N. J., and Lefkowitz, R. J. (1998) G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692.

    Article  CAS  PubMed  Google Scholar 

  170. 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.

    Article  CAS  PubMed  Google Scholar 

  171. Pippig, S., Andexinger, S., and Lohse, M. J. (1995) Sequestration and recycling of beta 2-adrenergic receptors permit receptor resensitization. Mol. Pharmacol. 47, 666–676.

    CAS  PubMed  Google Scholar 

  172. Koenig, J. A., and Edwardson, J. M. (1997) Endocytosis and recycling of G protein-coupled receptors. Trends Pharmacol. Sci. 18, 276–287.

    CAS  PubMed  Google Scholar 

  173. Barak, L. S., Tiberi, M., Freedman, N. J., Kwatra, M. M., Lefkowitz, R. J., and Caron, M. G. (1994) A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration. J. Biol. Chem. 269, 2790–2795.

    CAS  PubMed  Google Scholar 

  174. Gabilondo, A. M., Hegler, J., Krasel, C., Boivin-Jahns, V., Hein, L., and Lohse, M. J. (1997) A dileucine motif in the C terminus of the beta2-adrenergic receptor is involved in receptor internalization. Proc. Natl. Acad. Sci. U. S. A. 94, 12285–12290.

    Article  CAS  PubMed  Google Scholar 

  175. Preisser, L., Ancellin, N., Michaelis, L., Creminon, C., Morel, A., and Corman, B. (1999) Role of the carboxyl-terminal region, di-leucine motif and cysteine residues in signalling and internalization of vasopressin V1a receptor. FEBS Lett. 460, 303–308.

    Article  CAS  PubMed  Google Scholar 

  176. Benya, R. V., Fathi, Z., Battey, J. F., and Jensen, R. T. (1993) Serines and threonines in the gastrin-releasing peptide receptor carboxyl terminus mediate internalization. J. Biol. Chem. 268, 20285–20290.

    CAS  PubMed  Google Scholar 

  177. Roth, A., Kreienkamp, H. J., Meyerhof, W., and Richter, D. (1997) Phosphorylation of four amino acid residues in the carboxyl terminus of the rat somatostatin receptor subtype 3 is crucial for its desensitization and internalization. J. Biol. Chem. 272, 23769–23774.

    Article  CAS  PubMed  Google Scholar 

  178. Pizard, A., Blaukat, A., Muller-Esterl, W., Alhenc-Gelas, F., and Rajerison, R. M. (1999) Bradykinin-induced internalization of the human B2 receptor requires phosphorylation of three serine and two threonine residues at its carboxyl tail [in process citation]. J. Biol. Chem. 274, 12738–12747.

    Article  CAS  PubMed  Google Scholar 

  179. Kennelly, P. J., and Krebs, E. G. (1991) Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. J. Biol. Chem. 266, 15555–15558.

    CAS  PubMed  Google Scholar 

  180. Onorato, J. J., Palczewski, K., Regan, J. W., Caron, M. G., Lefkowitz, R. J., and Benovic, J. L. (1991) Role of acidic amino acids in peptide substrates of the beta-adrenergic receptor kinase and rhodopsin kinase. Biochemistry. 30, 5118–5125.

    Article  CAS  PubMed  Google Scholar 

  181. Inglese, J., Freedman, N. J., Koch, W. J., and Lefkowitz, R. J. (1993) Structure and mechanism of the G protein-coupled receptor kinases. J. Biol. Chem. 268, 23735–23738.

    CAS  PubMed  Google Scholar 

  182. Oppermann, M., Diverse-Pierluissi, M., Drazner, M. H., et al. (1996) Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases. Proc. Natl. Acad. Sci. U. S. A. 93, 7649–7654.

    Article  CAS  PubMed  Google Scholar 

  183. Chen, C. K., Zhang, K., Church-Kopish, J., et al. (2001) Characterization of human GRK7 as a potential cone opsin kinase. Mol. Vision. 7, 305–313.

    CAS  Google Scholar 

  184. Min, L., and Ascoli, M. (2000) Effect of activating and inactivating mutations on the phosphorylation and trafficking of the human lutropin/choriogonadotropin receptor. Mol. Endocrinol. 14, 1797–1810.

    Article  CAS  PubMed  Google Scholar 

  185. Loudon, R. P., and Benovic, J. L. (1994) Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6. J. Biol. Chem. 269, 22691–22697.

    CAS  PubMed  Google Scholar 

  186. Rankin, M. L., Marinec, P. S., Cabrera, D. M., Wang, Z., Jose, P. A., and Sibley, D. R. (2006) The D1 dopamine receptor is constitutively phosphorylated by G protein-coupled receptor kinase 4. Mol. Pharmacol. 69, 759–769.

    CAS  PubMed  Google Scholar 

  187. Yu, P., Asico, L. D., Luo, Y., et al. (2006) D1 dopamine receptor hyperphosphorylation in renal proximal tubules in hypertension. Kidney Int. 70, 1072–1079.

    Article  CAS  PubMed  Google Scholar 

  188. Felder, R. A., and Jose, P. A. (2006) Mechanisms of disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity. Nat. Clin. Pract. Nephrol. 2, 637–650.

    Article  CAS  PubMed  Google Scholar 

  189. Dryja, T. P. (2000) Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture. Am. J. Ophthalmol. 130, 547–563.

    Article  CAS  PubMed  Google Scholar 

  190. Sandberg, M. A., WeigelDiFranco, C., Rosner, B., and Berson, E. L. (1996) The relationship between visual field size and electroretinogram amplitude in retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 37, 1693–1698.

    CAS  PubMed  Google Scholar 

  191. Cideciyan, A. V., Zhao, X., Nielsen, L., Khani, S. C., Jacobson, S. G., and Palczewski, K. (1998) Null mutation in the rhodopsin kinase gene slows recovery kinetics of rod and cone phototransduction in man. Proc. Natl. Acad. Sci. U. S. A. 95, 328–333.

    Article  CAS  PubMed  Google Scholar 

  192. Shenker, A. (1995) G protein-coupled receptor structure and function: the impact of disease-causing mutations. Baillieres Clin. Endocrinol. Metab. 9, 427–451.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

A Canadian Institutes of Health Research/Epilepsy Canada postdoctoral research fellowship (M.D.T.) provided support for this work. This work was supported in part by grants from the National Science and Engineering Research Council (NSERC) and the Dairy Farmers of Canada (DFC). We thank Dr. Craig Behnke for permission to adapt the image presented in Fig. 6.1.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, Banting Institute, University of Toronto, Toronto, Ontario, Canada

    Miles D. Thompson & David E. C. Cole

  2. Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA

    Pedro A. Jose

Authors
  1. Miles D. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David E. C. Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pedro A. Jose
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. PharmTao, Santa Clara, CA, USA

    Qing Yan

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, a part of Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Thompson, M.D., Cole, D.E.C., Jose, P.A. (2008). Pharmacogenomics of G Protein-Coupled Receptor. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology™, vol 448. Humana Press. https://doi.org/10.1007/978-1-59745-205-2_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-205-2_6

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-887-4

  • Online ISBN: 978-1-59745-205-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation