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Genetic and Molecular Regulation of β2-Adrenergic Receptors

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Allergy Frontiers: Epigenetics, Allergens and Risk Factors

Part of the book series: Allergy Frontiers ((ALLERGY,volume 1))

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β2-adrenergic receptor agonists are bronchodilators used extensively in the treatment of asthma and other respiratory conditions associated with airflow limitation and obstruction. Both short-acting β2-adrenergic receptor agonists (SABA; e.g., salbutamol) and long-acting β2-adrenergic receptor agonists (LABA; e.g., formoterol) have been developed for acute relief from disease exacerbation or maintenance therapy, respectively.

The pharmacological target of β2-adrenergic receptor agonists is the β2-adrenergic receptor, a G-protein coupled receptor (GPCR) expressed on multiple cell types in the airways and systemically. In this chapter, we focus on the genetic and molecular mechanisms that regulate the expression and activity of this important drug target in the context of respiratory disease.

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References

  1. Kobilka, BK, Dixon, Frielle T, et al (1987) cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci USA 84(1):46–50.

    Article  PubMed  CAS  Google Scholar 

  2. Carstairs, JR, Nimmo AJ, Barnes PJ (1985) Autoradiographic visualization of beta-adrenocep-tor subtypes in human lung. Am Rev Respir Dis 132(3):541–547.

    PubMed  CAS  Google Scholar 

  3. Marone, G, Ambrosio G, Bonaduce D, Genovese A, Triggiani M, Condorelli M (1984) Inhibition of IgE-mediated histamine release from human basophils and mast cells by fenot-erol. Int Arch Allergy Appl Immunol 74(4):356–361.

    PubMed  CAS  Google Scholar 

  4. Kelsen, SG, Anakwe O, Aksoy MO, Reddy PJ, Dhanasekaran N (1997) IL-1 beta alters beta-adrenergic receptor adenylyl cyclase system function in human airway epithelial cells. Am J Physiol 273(3 Pt 1):L694–L700.

    PubMed  CAS  Google Scholar 

  5. Hayes, MJ, Qing F, Rhodes CG, et al (1996) In vivo quantification of human pulmonary beta-adrenoceptors: effect of beta-agonist therapy. Am J Respir Crit Care Med 154(5):1277–1283.

    PubMed  CAS  Google Scholar 

  6. Qing, F, Rahman SU, Rhodes CG, et al (1997) Pulmonary and cardiac beta-adrenoceptor density in vivo in asthmatic subjects. Am J Respir Crit Care Med 155(3):1130–1134.

    PubMed  CAS  Google Scholar 

  7. Qing, F, Rhodes CG, Hayes MJ, et al (1996) In vivo quantification of human pulmonary beta-adrenoceptor density using PET: comparison with in vitro radioligand binding. J Nucl Med 37(8):1275–1281.

    PubMed  CAS  Google Scholar 

  8. Strader, CD, Sigal IS, Candelore MR, Rands E, Hill WS, Dixon RA (1988) Conserved aspar-tic acid residues 79 and 113 of the beta-adrenergic receptor have different roles in receptor function. J Biol Chem 263(21):10267–10271.

    PubMed  CAS  Google Scholar 

  9. Strader, CD, Candelore MR, Hill WS, Sigal IS, Dixon RA (1989) Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor. J Biol Chem 264(23):13572–13578.

    PubMed  CAS  Google Scholar 

  10. Liapakis, G, Ballesteros JA, Papachristou S, Chan WC, Chen X, Javitch JA (2000) The forgotten serine. A critical role for Ser-2035.42 in ligand binding to and activation of the beta 2-adrenergic receptor. J Biol Chem 275(48):37779–37788.

    Article  PubMed  CAS  Google Scholar 

  11. Wieland, K, Zuurmond HM, Krasel C, Ijzerman AP, Lohse MJ (1996) Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor. Proc Natl Acad Sci USA 93(17):9276–9281.

    Article  Google Scholar 

  12. Freddolino, PL, Kalani M Y, Vaidehi N, et al (2004). Predicted 3D structure for the human beta 2 adrenergic receptor and its binding site for agonists and antagonists. Proc Natl Acad Sci USA 101(9):2736–2741.

    Article  PubMed  CAS  Google Scholar 

  13. Liggett SB (2002) Update on current concepts of the molecular basis of beta2-adrenergic receptor signaling. J Allergy Clin Immunol 110(6 Suppl):S223–S227.

    Article  PubMed  CAS  Google Scholar 

  14. Daaka, Y, Luttrell LM, Lefkowitz RJ (1997) Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 390(6655):88–91.

    Article  PubMed  CAS  Google Scholar 

  15. Liggett, SB, Bouvier M, Hausdorff WP, O'Dowd B, Caron MG, Lefkowitz RJ (1989) Altered patterns of agonist-stimulated cAMP accumulation in cells expressing mutant beta 2-adrener-gic receptors lacking phosphorylation sites. Mol Pharmacol 36(4):641–646.

    PubMed  CAS  Google Scholar 

  16. Iyer V, Tran TM, Foster E, Dai W, Clark RB, Knoll BJ (2006) Differential phosphorylation and dephosphorylation of beta2-adrenoceptor sites Ser262 and Ser355,356. Br J Pharmacol 147(3):249–59.

    Article  PubMed  CAS  Google Scholar 

  17. Johnson M (2006) Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 117(1):18–24; quiz 25.

    Article  PubMed  CAS  Google Scholar 

  18. Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294(5545):1307–1313.

    Article  PubMed  CAS  Google Scholar 

  19. Turki J, Green SA, Newman KB, Meyers MA, Liggett SB (1995) Human lung cell beta 2-adrenergic receptors desensitize in response to in vivo administered beta-agonist. Am J Physiol 269(5 Pt 1):L709–L714.

    PubMed  CAS  Google Scholar 

  20. Mialet-Perez J, Green SA, Miller WE, Liggett SB (2004) A primate-dominant third glycosylation site of the beta2-adrenergic receptor routes receptors to degradation during agonist regulation. J Biol Chem 279(37):38603–38607.

    Article  PubMed  CAS  Google Scholar 

  21. O'Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ, Bouvier M (1989) Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J Biol Chem 264(13):7564–7569.

    PubMed  Google Scholar 

  22. Sheppard JR, Wehner JM, McSwigan JD, Shows TB (1983) Chromosomal assignment of the gene for the human beta 2-adrenergic receptor. Proc Natl Acad Sci USA 80(1):233–236.

    Article  PubMed  CAS  Google Scholar 

  23. Parola AL, Kobilka BK (1994) The peptide product of a 5' leader cistron in the beta 2 adren-ergic receptor mRNA inhibits receptor synthesis. J Biol Chem 269(6):4497–4505.

    PubMed  CAS  Google Scholar 

  24. Emorine LJ, Marullo S, Delavier-Klutchko C, Kaveri S V, Durieu-Trautmann O, Strosberg AD (1987) Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization. Proc Natl Acad Sci USA 84(20):6995–6999.

    Article  PubMed  CAS  Google Scholar 

  25. Swan C, Richards SA, Duroudier NP, Sayers I, Hall IP (2006) Alternative promoter use and splice variation in the human histamine H1 receptor gene. Am J Respir Cell Mol Biol 35(1):118–126.

    Article  PubMed  CAS  Google Scholar 

  26. Duroudier NP, Sayers I, Castagna CC, et al (2007) Functional polymorphism and differential regulation of CYSLTR1 transcription in human airway smooth muscle and monocytes. Cell Biochem Biophys 47(1):119–130.

    PubMed  CAS  Google Scholar 

  27. Collins S, Bouvier M, Bolanowski MA, Caron MG, Lefkowitz RJ (1989) cAMP stimulates transcription of the beta 2-adrenergic receptor gene in response to short-term agonist exposure. Proc Natl Acad Sci USA 86(13):4853–4857.

    Article  PubMed  CAS  Google Scholar 

  28. Collins S, Altschmied J, Herbsman O, Caron MG, Mellon PL, Lefkowitz RJ (1990) A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP. J Biol Chem 265(31):19330–19335.

    PubMed  CAS  Google Scholar 

  29. Mak JC, Nishikawa M, Barnes PJ (1995) Glucocorticosteroids increase beta 2-adrenergic receptor transcription in human lung. Am J Physiol 268(1 Pt 1):L41– L46.

    PubMed  CAS  Google Scholar 

  30. Adcock IM, Maneechotesuwan K, Usmani O (2002) Molecular interactions between glucocor-ticoids and long-acting beta2-agonists. J Allergy Clin Immunol 110(6 Suppl):S261– S268.

    Article  PubMed  CAS  Google Scholar 

  31. Chung KF, Adcock IM (2004) Combination therapy of long-acting beta2-adrenoceptor agonists and corticosteroids for asthma. Treat Respir Med 3(5):279–289.

    Article  PubMed  CAS  Google Scholar 

  32. Usmani OS, Ito K, Maneechotesuwan K, et al (2005) Glucocorticoid receptor nuclear trans-location in airway cells after inhaled combination therapy. Am J Respir Crit Care Med 172(6):704–712.

    Article  PubMed  Google Scholar 

  33. Hancox RJ (2006) Interactions between corticosteroids and beta2-agonists. Clin Rev Allergy Immunol 31(2–3):231–246.

    Article  PubMed  CAS  Google Scholar 

  34. Danner S, Frank M, Lohse MJ (1998) Agonist regulation of human beta2-adrenergic receptor mRNA stability occurs via a specific AU-rich element. J Biol Chem 273(6):3223–3229.

    Article  PubMed  CAS  Google Scholar 

  35. Subramaniam K, Chen K, Joseph K, Raymond JR, Tholanikunnel BG (2004) The 3'-untranslated region of the beta2-adrenergic receptor mRNA regulates receptor synthesis. J Biol Chem 279(26):27108–27115.

    Article  PubMed  CAS  Google Scholar 

  36. Reihsaus E, Innis M, MacIntyre N, Liggett SB (1993) Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 8(3):334–339.

    PubMed  CAS  Google Scholar 

  37. McGraw DW, Forbes SL, Kramer LA, Liggett SB (1998) Polymorphisms of the 5' leader cistron of the human beta2-adrenergic receptor regulate receptor expression. J Clin Invest 102(11):1927–1932.

    Article  PubMed  CAS  Google Scholar 

  38. Scott MG, Swan C, Wheatley AP, Hall IP (1999) Identification of novel polymorphisms within the promoter region of the human beta2 adrenergic receptor gene. Br J Pharmacol 126(4):841–844.

    Article  PubMed  CAS  Google Scholar 

  39. Hawkins GA, Tantisira K, Meyers DA, et al (2006). Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study. Am J Respir Crit Care Med 174(10):1101–1109.

    Article  PubMed  CAS  Google Scholar 

  40. Green SA, Cole G, Jacinto M, Innis M, Liggett SB (1993) A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 268(31):23116–23121.

    PubMed  CAS  Google Scholar 

  41. Green SA, Turki J, Innis M, Liggett SB (1994) Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 33(32):9414–9419.

    Article  PubMed  CAS  Google Scholar 

  42. Green SA, Rathz DA, Schuster AJ, Liggett SB (2001) The Ile164 beta(2)-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to G(s). Eur J Pharmacol 421(3):141–147.

    Article  PubMed  CAS  Google Scholar 

  43. Moore PE, Laporte JD, Abraham JH, et al (2000). Polymorphism of the beta(2)-adrenergic receptor gene and desensitization in human airway smooth muscle. Am J Respir Crit Care Med 162(6):2117–2124.

    PubMed  CAS  Google Scholar 

  44. Lipworth B, Koppelman GH, Wheatley AP, et al (2002). Beta2 adrenoceptor promoter polymorphisms: Extended haplotypes and functional effects in peripheral blood mononuclear cells. Thorax 57(1):61–66.

    Article  PubMed  CAS  Google Scholar 

  45. Johnatty SE, Abdellatif M, Shimmin L, Clark RB, Boerwinkle E (2002) Beta 2 adrenergic receptor 5 haplotypes influence promoter activity. Br J Pharmacol 137(8):1213–1216.

    Article  PubMed  CAS  Google Scholar 

  46. Moore PE, Calder MM, Silverman ES, Panettieri RA Jr, Shore SA (2003) Effect of dexame-thasone on beta2-adrenergic desensitization in airway smooth muscle: Role of the ARG19 polymorphism. Chest 123(3 Suppl):368S–369S.

    Article  PubMed  Google Scholar 

  47. Panebra A, Schwarb MR, Glinka CB, Liggett SB (2007) Allele-specific binding of airway nuclear extracts to polymorphic beta2-adrenergic receptor 5 sequence. Am J Respir Cell Mol Biol 36(6):654–660.

    Article  PubMed  CAS  Google Scholar 

  48. Dishy V, Sofowora GG, Xie HG, et al (2001) The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 345(14):1030–1035.

    Article  PubMed  CAS  Google Scholar 

  49. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R (1997) Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 100(12):3184–3188.

    Article  PubMed  CAS  Google Scholar 

  50. Tan S, Hall IP, Dewar J, Dow E, Lipworth B (1997) Association between beta 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 350(9083):995–999.

    Article  PubMed  CAS  Google Scholar 

  51. Hancox RJ, Sears MR, Taylor DR (1998). Polymorphism of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma. Eur Respir J 11(3):589–593.

    PubMed  CAS  Google Scholar 

  52. Lipworth BJ, Hall IP, Aziz I, Tan KS, Wheatley A (1999) Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta2-agonist therapy. Clin Sci (Lond) 96(3):253–259.

    Article  CAS  Google Scholar 

  53. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self TH, Johnson JA (1999) Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharma-codynamics. Clin Pharmacol Ther 65(5):519–525.

    Article  PubMed  CAS  Google Scholar 

  54. Israel E, Drazen JM, Liggett SB, et al (2000) The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 162(1):75–80.

    PubMed  CAS  Google Scholar 

  55. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI (2000) Asthma exacerbations during long term beta agonist use: Influence of beta(2) adrenoceptor polymorphism. Thorax 55(9): 762–767.

    Article  PubMed  CAS  Google Scholar 

  56. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ (2004) The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formot-erol and salmeterol. Br J Clin Pharmacol 57(1):68–75.

    Article  PubMed  CAS  Google Scholar 

  57. Israel E, Chinchilli VM, Ford JG, et al (2004). Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 364(9444):1505–1512.

    Article  PubMed  CAS  Google Scholar 

  58. Aziz I, Hall IP, McFarlane LC, Lipworth BJ (1998) Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol 101(3):337–341.

    Article  PubMed  CAS  Google Scholar 

  59. Wechsler ME, Lehman E, Lazarus SC, et al (2006) Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 173(5):519–526.

    Article  PubMed  CAS  Google Scholar 

  60. Drysdale CM, McGraw DW, Stack CB, et al (2000) Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 97(19):10483–10488.

    Article  PubMed  CAS  Google Scholar 

  61. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM (2006) The Salmeterol Multicenter Asthma Research Trial: A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 129(1):15–26.

    Article  PubMed  CAS  Google Scholar 

  62. Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP (2005) Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol 115(5):963–972.

    Article  PubMed  CAS  Google Scholar 

  63. Thakkinstian A, McEvoy M, Minelli C, et al (2005) Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: A HuGE review. Am J Epidemiol 162(3):201–211.

    Article  PubMed  Google Scholar 

  64. Hall IP, Blakey JD, Al Balushi KA, et al (2006) Beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: A genetic association study. Lancet 368(9537):771–779.

    Article  PubMed  CAS  Google Scholar 

  65. Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M (2007) Effect of indacaterol, a novel long-acting beta2-agonist, on isolated human bronchi. Eur Respir J 29(3):575–581.

    Article  PubMed  CAS  Google Scholar 

  66. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB (1995) Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 13(1):25–33.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, NG7 2UH, UK

    Ian Sayers & Ian P. Hall

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  1. Ian Sayers
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  1. Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan

    Ruby Pawankar

  2. Childrens's Mercy Hospital & Clinic, 2401 Gillham RD, Kansas city, MO, USA

    Stephen T. Holgate

  3. Southampton General Hospital, University of Southampton, Tremona Road, Southampton, UK

    Lanny J. Rosenwasser

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Sayers, I., Hall, I.P. (2009). Genetic and Molecular Regulation of β2-Adrenergic Receptors. In: Pawankar, R., Holgate, S.T., Rosenwasser, L.J. (eds) Allergy Frontiers: Epigenetics, Allergens and Risk Factors. Allergy Frontiers, vol 1. Springer, Tokyo. https://doi.org/10.1007/978-4-431-72802-3_12

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  • DOI: https://doi.org/10.1007/978-4-431-72802-3_12

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