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Article: Albuterol-induced downregulation of Gsα accounts for pulmonary β2- adrenoceptor desensitization in vivo

TitleAlbuterol-induced downregulation of Gsα accounts for pulmonary β2- adrenoceptor desensitization in vivo
Authors
Issue Date2000
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal Of Clinical Investigation, 2000, v. 106 n. 1, p. 125-135 How to Cite?
AbstractThe aim of the present study was to develop a chronic in vivo model of pulmonary β2-adrenoceptor desensitization and to elucidate the nature and molecular basis of this state. Subcutaneous infusion of rats with albuterol for 7 days compromised the ability of albuterol, given acutely, to protect against acetylcholine-induced bronchoconstriction. The bronchoprotective effect of prostaglandin E2, but not forskolin, was also impaired, indicating that the desensitization was heterologous and that the primary defect in signaling was upstream of adenylyl cyclase. β2-Adrenoceptor density was reduced in lung membranes harvested from albuterol-treated animals, and this was associated with impaired albuterol-induced cyclic adenosine monophosphate (cAMP) accumulation and activation of cAMP-dependent protein kinase ex vivo. Gsα expression was reduced in the lung and tracheae of albuterol-treated rats, and cholera toxin-induced cAMP accumulation was blunted. Chronic treatment of rats with albuterol also increased cAMP phosphodiesterase activity and G protein-coupled receptor kinase-2, but the extent to which these events contributed to β2-adrenoceptor desensitization was unclear given that forskolin was active in both groups of animals and that desensitization was heterologous. Collectively, these results indicate that albuterol effects heterologous desensitization of pulmonary Gs-coupled receptors in this model, with downregulation of Gsα representing a primary molecular etiology.
Persistent Identifierhttp://hdl.handle.net/10722/162397
ISSN
2015 Impact Factor: 12.575
2015 SCImago Journal Rankings: 8.764
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorFinney, PAen_US
dc.contributor.authorBelvisi, MGen_US
dc.contributor.authorDonnelly, LEen_US
dc.contributor.authorChuang, TTen_US
dc.contributor.authorMak, JCWen_US
dc.contributor.authorScorer, Cen_US
dc.contributor.authorBarnes, PJen_US
dc.contributor.authorAdcock, IMen_US
dc.contributor.authorGiembycz, MAen_US
dc.date.accessioned2012-09-05T05:19:34Z-
dc.date.available2012-09-05T05:19:34Z-
dc.date.issued2000en_US
dc.identifier.citationJournal Of Clinical Investigation, 2000, v. 106 n. 1, p. 125-135en_US
dc.identifier.issn0021-9738en_US
dc.identifier.urihttp://hdl.handle.net/10722/162397-
dc.description.abstractThe aim of the present study was to develop a chronic in vivo model of pulmonary β2-adrenoceptor desensitization and to elucidate the nature and molecular basis of this state. Subcutaneous infusion of rats with albuterol for 7 days compromised the ability of albuterol, given acutely, to protect against acetylcholine-induced bronchoconstriction. The bronchoprotective effect of prostaglandin E2, but not forskolin, was also impaired, indicating that the desensitization was heterologous and that the primary defect in signaling was upstream of adenylyl cyclase. β2-Adrenoceptor density was reduced in lung membranes harvested from albuterol-treated animals, and this was associated with impaired albuterol-induced cyclic adenosine monophosphate (cAMP) accumulation and activation of cAMP-dependent protein kinase ex vivo. Gsα expression was reduced in the lung and tracheae of albuterol-treated rats, and cholera toxin-induced cAMP accumulation was blunted. Chronic treatment of rats with albuterol also increased cAMP phosphodiesterase activity and G protein-coupled receptor kinase-2, but the extent to which these events contributed to β2-adrenoceptor desensitization was unclear given that forskolin was active in both groups of animals and that desensitization was heterologous. Collectively, these results indicate that albuterol effects heterologous desensitization of pulmonary Gs-coupled receptors in this model, with downregulation of Gsα representing a primary molecular etiology.en_US
dc.languageengen_US
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.orgen_US
dc.relation.ispartofJournal of Clinical Investigationen_US
dc.subject.mesh1-Methyl-3-Isobutylxanthine - Pharmacologyen_US
dc.subject.mesh3',5'-Cyclic-Amp Phosphodiesterases - Metabolismen_US
dc.subject.meshAcetylcholine - Pharmacologyen_US
dc.subject.meshAdrenergic Beta-Agonists - Pharmacologyen_US
dc.subject.meshAlbuterol - Pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBronchoconstriction - Drug Effectsen_US
dc.subject.meshCyclic Amp - Physiologyen_US
dc.subject.meshCyclic Amp-Dependent Protein Kinases - Metabolismen_US
dc.subject.meshDinoprostone - Pharmacologyen_US
dc.subject.meshDown-Regulationen_US
dc.subject.meshGtp-Binding Protein Alpha Subunits, Gs - Physiologyen_US
dc.subject.meshLung - Chemistry - Drug Effectsen_US
dc.subject.meshMaleen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshReceptors, Adrenergic, Beta-2 - Analysis - Drug Effectsen_US
dc.titleAlbuterol-induced downregulation of Gsα accounts for pulmonary β2- adrenoceptor desensitization in vivoen_US
dc.typeArticleen_US
dc.identifier.emailMak, JCW:judymak@hku.hken_US
dc.identifier.authorityMak, JCW=rp00352en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1172/JCI8374-
dc.identifier.pmid10880056en_US
dc.identifier.scopuseid_2-s2.0-0033917738en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0033917738&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume106en_US
dc.identifier.issue1en_US
dc.identifier.spage125en_US
dc.identifier.epage135en_US
dc.identifier.isiWOS:000088103700016-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridFinney, PA=7003602458en_US
dc.identifier.scopusauthoridBelvisi, MG=35400532900en_US
dc.identifier.scopusauthoridDonnelly, LE=7102000743en_US
dc.identifier.scopusauthoridChuang, TT=7202737767en_US
dc.identifier.scopusauthoridMak, JCW=7103323094en_US
dc.identifier.scopusauthoridScorer, C=6701564019en_US
dc.identifier.scopusauthoridBarnes, PJ=36064679400en_US
dc.identifier.scopusauthoridAdcock, IM=7007066538en_US
dc.identifier.scopusauthoridGiembycz, MA=7007035171en_US

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