HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplement Table All Versions of this Article: 27/2/171    most recent 00044.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by McGraw, D. W. Articles by Liggett, S. B. Search for Related Content PubMed PubMed Citation Articles by McGraw, D. W. Articles by Liggett, S. B.

Transcriptional response to persistent ß₂-adrenergic receptor signaling reveals regulation of phospholamban, which alters airway contractility

¹ Pulmonary and Critical Care Medicine, University of Cincinnati College of Medicine, Cincinnati
² Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio
³ Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts
⁴ Departments of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio
⁵ Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Maryland

ß₂-Adrenergic receptors (ß₂AR) are expressed on airway smooth muscle cells and act to relax the airway on activation by ß-agonists. These agents are utilized for treating asthma but are associated with adverse outcomes. To ascertain the effects of persistent ß₂AR activation on gene expression, cultured airway smooth muscle cells derived from wild-type (WT) and transgenic mice overexpressing ß₂AR 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 Ca²⁺ concentration ([Ca²⁺]_i)-handling protein that is at a signaling nodal point in cardiomyocytes, was observed in ß₂AR-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^–/– mice. PLN^–/– mice had a markedly reduced constrictive response to methacholine. In contrast, the bronchodilatory effect of ß-agonist was not different between WT and PLN^–/– mice. These results revealed an unanticipated therapeutic effect of ß-agonists, PLN downregulation, which acts to decrease airway hyperreactivity. Thus agents that inhibit PLN may act synergistically with the bronchodilating action of ß-agonists. A number of other genes related to [Ca²⁺]_i are also differentially regulated by ß₂AR activity, some of which may act to oppose, or augment, the efficacy of chronic ß-agonists. These genes or pathways may also represent additional targets in the treatment of asthma and related obstructive lung diseases.

G protein-coupled receptors; asthma; ß-agonist

This article has been cited by other articles:

				V. Sathish, M. A. Thompson, J. P. Bailey, C. M. Pabelick, Y. S. Prakash, and G. C. Sieck Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+ reuptake in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, July 1, 2009; 297(1): L26 - L34. [Abstract] [Full Text] [PDF]

				S. M. Swift, B. R. Gaume, K. M. Small, B. J. Aronow, and S. B. Liggett Differential coupling of Arg- and Gly389 polymorphic forms of the {beta}1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs Physiol Genomics, September 17, 2008; 35(1): 123 - 131. [Abstract] [Full Text] [PDF]

				V. Sathish, F. Leblebici, S. N. Kip, M. A. Thompson, C. M. Pabelick, Y. S. Prakash, and G. C. Sieck Regulation of sarcoplasmic reticulum Ca2+ reuptake in porcine airway smooth muscle Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L787 - L796. [Abstract] [Full Text] [PDF]

				P. G. Woodruff Gene Expression in Asthmatic Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 113 - 118. [Abstract] [Full Text] [PDF]