Abstract
The obstructive lung disease asthma is treated by drugs that target, either directly or indirectly, G protein-coupled receptors (GPCRs). GPCRs coupled to Gq are the primary mediators of airway smooth muscle (ASM) contraction and increased airway resistance, whereas the Gs-coupled beta-2-adrenoceptor (β2AR) promotes pro-relaxant signaling in and relaxation of ASM resulting in greater airway patency and reversal of life-threatening bronchoconstriction. In addition, GPCR-mediated functions in other cell types, including airway epithelium and hematopoietic cells, are involved in the control of lung inflammation that causes most asthma. The capacity of arrestins to regulate GPCR signaling, via either control of GPCR desensitization/resensitization or G protein-independent signaling, renders arrestins an intriguing therapeutic target for asthma and other obstructive lung diseases. This review will focus on the potential role of arrestins in those GPCR-mediated airway cell functions that are dysregulated in asthma.
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Ahlquist RP (1948a) A study of the adrenotropic receptors. Am J Physiol 153:586–600
Ahlquist RP (1948b) Comparative effects of sympathomimetic amines on the vasomotor resistance of the kidney, mesentery and leg. Fed Proc 7:202
An SS, Bai TR, Bates JH, Black JL, Brown RH, Brusasco V, Chitano P, Deng L, Dowell M, Eidelman DH, Fabry B, Fairbank NJ, Ford LE, Fredberg JJ, Gerthoffer WT, Gilbert SH, Gosens R, Gunst SJ, Halayko AJ, Ingram RH, Irvin CG, James AL, Janssen LJ, King GG, Knight DA, Lauzon AM, Lakser OJ, Ludwig MS, Lutchen KR, Maksym GN, Martin JG, Mauad T, McParland BE, Mijailovich SM, Mitchell HW, Mitchell RW, Mitzner W, Murphy TM, Pare PD, Pellegrino R, Sanderson MJ, Schellenberg RR, Seow CY, Silveira PS, Smith PG, Solway J, Stephens NL, Sterk PJ, Stewart AG, Tang DD, Tepper RS, Tran T, Wang L (2007) Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. Eur Respir J 29:834–860
Barnes PJ (2006) Drugs for asthma. Br J Pharmacol 147(Suppl 1):S297–S303
Billington CK, Penn RB (2003) Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res 4:2
Billington CK, Ojo OO, Penn RB, Ito S (2013) cAMP regulation of airway smooth muscle function. Pulm Pharmacol Ther 26(1):112–120
Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M (2007) Effect of ADRB2 polymorphisms on response to long acting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 370:2118–2125
Bond RA (2001) Is paradoxical pharmacology a strategy worth pursuing? Trends Pharmacol Sci 22:273–276
Bradbury NA, Dormer RL, McPherson MA (1990) Dissociation between cyclic AMP rise and mucin secretion in response to a beta-adrenergic agonist. Acta Univ Carol Med 36:55–57
Callaerts-Vegh Z, Evans KL, Dudekula N, Cuba D, Knoll BJ, Callaerts PF, Giles H, Shardonofsky FR, Bond RA (2004) Effects of acute and chronic administration of beta-adrenoceptor ligands on airway function in a murine model of asthma. Proc Natl Acad Sci USA 101:4948–4953
Canning BJ, Fischer A (2001) Neural regulation of airway smooth muscle tone. Respir Physiol 125:113–127
Castle W, Fuller R, Hall J, Palmer J (1993) Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 306:1034–1037
Deshpande DA, Penn RB (2006) Targeting G protein-coupled receptor signaling in asthma. Cell Signal 18:2105–2120
Deshpande DA, Pascual RM, Wang SW, Eckman DM, Riemer EC, Funk CD, Penn RB (2007) PKC-dependent regulation of the receptor locus dominates functional consequences of cysteinyl leukotriene type 1 receptor activation. FASEB J 21:2335–2342
Deshpande DA, Theriot BS, Penn RB, Walker JK (2008) {beta}-Arrestins specifically constrain {beta}2-adrenergic receptor signaling and function in airway smooth muscle. FASEB J 22:2134–2141
Grainger J, Woodman K, Pearce N, Crane J, Burgess C, Keane A, Beasley R (1991) Prescribed fenoterol and death from asthma in New Zealand, 1981–7: a further case–control study. Thorax 46:105–111
Gray T, Nettesheim P, Loftin C, Koo JS, Bonner J, Peddada S, Langenbach R (2004) Interleukin-1beta-induced mucin production in human airway epithelium is mediated by cyclooxygenase-2, prostaglandin E2 receptors, and cyclic AMP-protein kinase A signaling. Mol Pharmacol 66:337–346
Hall IP, Blakey JD, Al Balushi KA, Wheatley A, Sayers I, Pembrey ME, Ring SM, McArdle WL, Strachan DP (2006) Beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study. Lancet 368:771–779
Hanania NA, Singh S, El-Wali R, Flashner M, Franklin AE, Garner WJ, Dickey BF, Parra S, Ruoss S, Shardonofsky F, O’Connor BJ, Page C, Bond RA (2008) The safety and effects of the beta-blocker, nadolol, in mild asthma: an open-label pilot study. Pulm Pharmacol Ther 21(1):134–141
Hanania NA, Dickey BF, Bond RA (2010) Clinical implications of the intrinsic efficacy of beta-adrenoceptor drugs in asthma: full, partial and inverse agonism. Curr Opin Pulm Med 16:1–5
Hollingsworth JW, Theriot BS, Li Z, Lawson BL, Sunday M, Schwartz DA, Walker JK (2010) Both hematopoietic-derived and non-hematopoietic-derived {beta}-arrestin-2 regulates murine allergic airway disease. Am J Respir Cell Mol Biol 43:269–275
Jacoby DB, Gleich GJ, Fryer AD (1993) Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. J Clin Invest 91:1314–1318
Kiyingi KS, Anderson SD, Temple DM, Shaw J (1985) Beta-adrenoceptor blockade with propranolol and bronchial responsiveness to a number of bronchial provocation tests in non-asthmatic subjects. Eur J Respir Dis 66:256–267
Kong KC, Gandhi U, Martin TJ, Anz CB, Yan H, Misior AM, Pascual RM, Deshpande DA, Penn RB (2008) Endogenous Gs-coupled receptors in smooth muscle exhibit differential susceptibility to GRK2/3-mediated desensitization. Biochemistry 47:9279–9288
Kotlikoff MI, Kamm KE (1996) Molecular mechanisms of beta-adrenergic relaxation of airway smooth muscle. Annu Rev Physiol 58:115–141
Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown TGJ (1967) Differentiation of receptor systems activated by sympathomimetic amines. Nature 214:597–598
Lin R, Degan S, Theriot BS, Fischer BM, Strachan RT, Liang J, Pierce RA, Sunday ME, Noble PW, Kraft M, Brody AR, Walker JK (2012) Chronic treatment in vivo with beta-adrenoceptor agonists induces dysfunction of airway beta(2)-adrenoceptors and exacerbates lung inflammation in mice. Br J Pharmacol 165:2365–2377
Luo J, Busillo JM, Benovic JL (2008) M3 muscarinic acetylcholine receptor-mediated signaling is regulated by distinct mechanisms. Mol Pharmacol 74:338–347
Luttrell LM, Gesty-Palmer D (2010) Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev 62:305–330
Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von ME, Farrall M, Lathrop M, Cookson WO (2010) A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 363:1211–1221
Morwood K, Gillis D, Smith W, Kette F (2005) Aspirin-sensitive asthma. Intern Med J 35:240–246
Naik S, Billington CK, Pascual RM, Deshpande DA, Stefano FP, Kohout TA, Eckman DM, Benovic JL, Penn RB (2005) Regulation of cysteinyl leukotriene type 1 receptor internalization and signaling. J Biol Chem 280:8722–8732
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 129:15–26
Nguyen LP, Omoluabi O, Parra S, Frieske JM, Clement C, Ammar-Aouchiche Z, Ho SB, Ehre C, Kesimer M, Knoll BJ, Tuvim MJ, Dickey BF, Bond RA (2008) Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model. Am J Respir Cell Mol Biol 38:256–262
Nguyen LP, Lin R, Parra S, Omoluabi O, Hanania NA, Tuvim MJ, Knoll BJ, Dickey BF, Bond RA (2009) Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model. Proc Natl Acad Sci USA 106:2435–2440
Nichols HL, Saffeddine M, Theriot BS, Hegde A, Polley D, El-Mays T, Vliagoftis H, Hollenberg MD, Wilson EH, Walker JK, DeFea KA (2012) beta-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proc Natl Acad Sci USA 109:16660–16665
Paterson, Lulich K, Goldie R (1984) Drug effects on beta-adrenergic receptor function in asthma. In: Morley J (ed) Beta-adrenoceptors in asthma. Academic, London, pp 245–268
Pearce N, Beasley R, Crane J, Burgess C, Jackson R (1995) End of the New Zealand asthma mortality epidemic. Lancet 345:41–44
Penn RB, Panettieri RA Jr, Benovic JL (1998) Mechanisms of acute desensitization of the β2AR-adenylyl cyclase pathway in human airway smooth muscle. Am J Respir Cell Mol Biol 19:338–348
Penn RB, Pascual RM, Kim Y-M, Mundell SJ, Krymskaya VP, Panettieri RA Jr, Benovic JL (2001) Arrestin specificity for G protein-coupled receptors in human airway smooth muscle. J Biol Chem 276:32648–32656
Robin Taylor D (2009) The Β-agonist saga and its clinical relevance: on and on it goes. Am J Respir Crit Care Med 179:976–978
Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE (2006) Meta-analysis: effect of long-acting {beta}-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 144:904–912
Sayers I, Hall IP (2005) Pharmacogenetic approaches in the treatment of asthma. Curr Allergy Asthma Rep 5:101–108
Sears MR (2002) Adverse effects of beta-agonists. J Allergy Clin Immunol 110:S322–S328
Sears MR, Taylor DR, Print CG, Lake DC, Li Q, Flannery EM, Yates DM, Lucas MK, Herbison GP (1990) Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 336:1391–1396
Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, Boivin JF, McNutt M, Buist AS, Rebuck AS (1992) The use of Β-agonists and the risk of death and near death from asthma. N Engl J Med 326:501–506
Stephens NL (2001) Airway smooth muscle. Lung 179:333–373
Stolley PD (1972) Asthma mortality. Why the United States was spared an epidemic of deaths due to asthma. Am Rev Respir Dis 105:883–890
Stolley PD, Schinnar R (1978) Association between asthma mortality and isoproterenol aerosols: a review. Prev Med 7:519–538
Szentivanyi A (1968) The beta-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 42:203–232
Tilley SL, Hartney JM, Erikson CJ, Jania C, Nguyen M, Stock J, McNeisch J, Valancius C, Panettieri RA Jr, Penn RB, Koller BH (2003) Receptors and pathways mediating the effects of prostaglandin E2 on airway tone. Am J Physiol Lung Cell Mol Physiol 284:599–606
van der Velden VH, Hulsmann AR (1999) Autonomic innervation of human airways: structure, function, and pathophysiology in asthma. Neuroimmunomodulation 6:145–159
Vatrella A, Parrella R, Pelaia G, Biscione GL, Tranfa CM, De Sarro GB, Bariffi F, Marsico SA (2001) Effects of non-bronchoconstrictive doses of inhaled propranolol on airway responsiveness to methacholine. Eur J Clin Pharmacol 57:99–104
Walker JK, Fong AM, Lawson BL, Savov JD, Patel DD, Schwartz DA, Lefkowitz RJ (2003) Beta-arrestin-2 regulates the development of allergic asthma. J Clin Invest 112:566–574
Walker JK, Penn RB, Hanania NA, Dickey BF, Bond RA (2011) New perspectives regarding beta(2) -adrenoceptor ligands in the treatment of asthma. Br J Pharmacol 163:18–28
Widdicombe JG (1998) Autonomic regulation. i-NANC/e-NANC. Am J Respir Crit Care Med 158:171–175
Yan H, Deshpande DA, Misior AM, Miles MC, Saxena H, Riemer EC, Pascual RM, Panettieri RA, Penn RB (2011) Anti-mitogenic effects of beta-agonists and PGE2 on airway smooth muscle are PKA dependent. FASEB J 25:389–397
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Work in the authors’ lab is funded by HL58506, P01 HL114471 (RBP), HL93013 (RBP and JKLW), HL084123 (JKLW), and AI079236 (JKLW and RAB).
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Penn, R.B., Bond, R.A., Walker, J.K.L. (2014). GPCRs and Arrestins in Airways: Implications for Asthma. In: Gurevich, V. (eds) Arrestins - Pharmacology and Therapeutic Potential. Handbook of Experimental Pharmacology, vol 219. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-41199-1_20
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