{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T20:02:25Z","timestamp":1774123345887,"version":"3.50.1"},"reference-count":30,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiological Genomics"],"published-print":{"date-parts":[[2006,10]]},"abstract":"\n \u03b2\n 2<\/jats:sub>\n -Adrenergic receptors (\u03b2\n 2<\/jats:sub>\n AR) are expressed on airway smooth muscle cells and act to relax the airway on activation by \u03b2-agonists. These agents are utilized for treating asthma but are associated with adverse outcomes. To ascertain the effects of persistent \u03b2\n 2<\/jats:sub>\n AR activation on gene expression, cultured airway smooth muscle cells derived from wild-type (WT) and transgenic mice overexpressing \u03b2\n 2<\/jats:sub>\n AR were subjected to DNA microarray analysis; 319 genes were increased and 164 were decreased. Differential expression was observed in genes from 22 Gene Ontology Slim categories, including those associated with ion transport and calcium ion binding. A 60% decrease ( P = 0.008) in phospholamban (PLN), an intracellular Ca\n 2+<\/jats:sup>\n concentration ([Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n )-handling protein that is at a signaling nodal point in cardiomyocytes, was observed in \u03b2\n 2<\/jats:sub>\n AR-overexpressing cells and confirmed at the protein level. To isolate the physiological effect of decreased PLN in airway smooth muscle, airway contraction and relaxation responses were studied in WT and PLN\n \u2212\/\u2212<\/jats:sup>\n mice. PLN\n \u2212\/\u2212<\/jats:sup>\n mice had a markedly reduced constrictive response to methacholine. In contrast, the bronchodilatory effect of \u03b2-agonist was not different between WT and PLN\n \u2212\/\u2212<\/jats:sup>\n mice. These results revealed an unanticipated therapeutic effect of \u03b2-agonists, PLN downregulation, which acts to decrease airway hyperreactivity. Thus agents that inhibit PLN may act synergistically with the bronchodilating action of \u03b2-agonists. A number of other genes related to [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n are also differentially regulated by \u03b2\n 2<\/jats:sub>\n AR activity, some of which may act to oppose, or augment, the efficacy of chronic \u03b2-agonists. These genes or pathways may also represent additional targets in the treatment of asthma and related obstructive lung diseases.\n <\/jats:p>","DOI":"10.1152\/physiolgenomics.00044.2006","type":"journal-article","created":{"date-parts":[[2006,7,18]],"date-time":"2006-07-18T20:49:00Z","timestamp":1153255740000},"page":"171-177","source":"Crossref","is-referenced-by-count":20,"title":["Transcriptional response to persistent \u03b2\n 2<\/sub>\n -adrenergic receptor signaling reveals regulation of phospholamban, which alters airway contractility"],"prefix":"10.1152","volume":"27","author":[{"given":"Dennis W.","family":"McGraw","sequence":"first","affiliation":[{"name":"Pulmonary and Critical Care Medicine, University of Cincinnati College of Medicine, Cincinnati"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M.","family":"Fogel","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, University of Cincinnati College of Medicine, Cincinnati"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sue","family":"Kong","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Augusto A.","family":"Litonjua","sequence":"additional","affiliation":[{"name":"Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelia G.","family":"Kranias","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce J.","family":"Aronow","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen B.","family":"Liggett","sequence":"additional","affiliation":[{"name":"Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.2001.6.1.19"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-6749(99)70270-8"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00061.2001"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2004.10.004"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000117254.68497.39"},{"key":"R6","doi-asserted-by":"crossref","unstructured":"Green SA\n , Cole G, Jacinto M, Innis M, and Liggett SB.\n A polymorphism of the human \u03b2\n 2\n -adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor.\n J Biol Chem\n 268\n : 23116\u201323121, 1993.","DOI":"10.1016\/S0021-9258(19)49434-9"},{"key":"R7","unstructured":"Green SA\n and Liggett SB.\n G protein coupled receptor signalling in the lung. In:\n The Genetics of Asthma\n . New York: Marcel Dekker, 1996, p. 67\u201390."},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.07.164"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510519103"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1540\/jsmr.40.219"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1139\/y05-070"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.278.2.C235"},{"key":"R13","unstructured":"Kraan J\n , Koeter GH, van der Mark TW, Sluiter HJ, and De Vries K.\n Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline.\n J Allergy Clin Immunol\n 76\n : 636\u2013636, 1985."},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.154.2.8756801"},{"key":"R15","unstructured":"Liggett SB\n and Green SA.\n Molecular biology of the \u03b2\n 2\n -adrenergic receptor: focus on interactions of agonist with receptor. In:\n \n \u03b2\n 2\n -Agonists in Asthma Treatment\n \n . New York: Marcel Dekker, 1996, p. 19\u201334."},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.75.3.401"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1151"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18193"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.45.32241"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1126\/science.8160017"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1378\/chest.129.1.15"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1139\/y05-075"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006889200"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1126\/science.1081578"},{"key":"R25","unstructured":"Sears MR\n .\n Role of \u03b2-agonists in asthma fatalities. In:\n Fatal Asthma\n . 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