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2-adrenergic receptor signaling reveals regulation of phospholamban which alters airway contractility
1 Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
2 Medicine, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States
3 Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
4 Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, United States
5 Pharmacology, University of Cincinatti, Cincinnati, Ohio, United States
6 Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: sligg001{at}umaryland.edu.
2-adrenergic receptors (2AR) are expressed on airway smooth muscle cells and act to relax the airway upon activation by -agonists. These agents are utilized for treating asthma, but are associated with adverse outcomes. To ascertain the effects of persistent 2AR activation on gene expression, cultured airway smooth muscle cells derived from wild-type and transgenic mice overexpressing 2AR were subjected to DNA microarray analysis; 319 genes were increased and 164 were decreased. Differential expression was observed in genes from 22 GO Slim categories, including those associated with ion transport and calcium ion binding. A 60% decrease (P=0.008) in PLN, a [Ca2+]i-handling protein which is at a signaling nodal point in cardiomyocytes, was observed in 2AR overexpressing cells and confirmed at the protein level. To isolate the physiologic 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 -agonist was not different between WT and PLN-/- mice. These results revealed an unanticipated therapeutic effect of -agonists, PLN downregulation, which acts to decrease airway hyperreactivity. Thus agents that inhibit PLN may act synergistically with the bronchodilating action of -agonists. A number of other genes related to [Ca2+]i are also differentially regulated by 2AR activity some of which may act to oppose, or augment, the efficacy of chronic -agonists. These genes or pathways may also represent additional targets in the treatment of asthma and related obstructive lung diseases.
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