TAS2R activation promotes airway smooth muscle relaxation despite β2-adrenergic receptor tachyphylaxis
Identifieur interne : 001451 ( Main/Exploration ); précédent : 001450; suivant : 001452TAS2R activation promotes airway smooth muscle relaxation despite β2-adrenergic receptor tachyphylaxis
Auteurs : Steven S. An [États-Unis] ; Wayne C. H. Wang [États-Unis] ; Cynthia J. Koziol-White [États-Unis] ; Kwangmi Ahn [États-Unis] ; Danielle Y. Lee [États-Unis] ; Richard C. Kurten [États-Unis] ; Reynold A. Jr Panettieri [États-Unis] ; Stephen B. Liggett [États-Unis]Source :
- American journal of physiology. Lung cellular and molecular physiology [ 1040-0605 ] ; 2012.
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- Pascal (Inist)
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Abstract
Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca2+ concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic β-agonists. The β2-adrenergic receptor (β2AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of β2AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of β2AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca2+ concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, β2AR desensitization by β-agonist amounted to 92 ± 6.0% (P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic β-agonist exposure culminated in 64 ± 5.7% (P < 0.001) desensitization of β2AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic P-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.
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An</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Program in Respiratory Biology and Lung Disease, Johns Hopkins University, Bloomberg School of Public Health</s1><s2>Baltimore, Maryland</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Wang, Wayne C H" sort="Wang, Wayne C H" uniqKey="Wang W" first="Wayne C. H." last="Wang">Wayne C. H. Wang</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Medicine, University of Maryland School of Medicine</s1><s2>Baltimore, Maryland</s2><s3>USA</s3><sZ>2 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Koziol White, Cynthia J" sort="Koziol White, Cynthia J" uniqKey="Koziol White C" first="Cynthia J." last="Koziol-White">Cynthia J. Koziol-White</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Division of Pulmonary, Allergy and Critical Care, Airways Biology Initiative, University of Pennsylvania Medical Center</s1><s2>Philadelphia, Pennsylvania</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Ahn, Kwangmi" sort="Ahn, Kwangmi" uniqKey="Ahn K" first="Kwangmi" last="Ahn">Kwangmi Ahn</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>National Institutes of Health</s1><s2>Bethesda, Maryland</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Lee, Danielle Y" sort="Lee, Danielle Y" uniqKey="Lee D" first="Danielle Y." last="Lee">Danielle Y. Lee</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Program in Respiratory Biology and Lung Disease, Johns Hopkins University, Bloomberg School of Public Health</s1><s2>Baltimore, Maryland</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Kurten, Richard C" sort="Kurten, Richard C" uniqKey="Kurten R" first="Richard C." last="Kurten">Richard C. Kurten</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Department of Physiology and Biophysics, University of Arkansas for Medical Sciences</s1><s2>Little Rock, Arkansas</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Arkansas</region></placeName></affiliation></author><author><name sortKey="Panettieri, Reynold A Jr" sort="Panettieri, Reynold A Jr" uniqKey="Panettieri R" first="Reynold A. Jr" last="Panettieri">Reynold A. Jr Panettieri</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Division of Pulmonary, Allergy and Critical Care, Airways Biology Initiative, University of Pennsylvania Medical Center</s1><s2>Philadelphia, Pennsylvania</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Liggett, Stephen B" sort="Liggett, Stephen B" uniqKey="Liggett S" first="Stephen B." last="Liggett">Stephen B. Liggett</name><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Personalized Medicine Institute, University of South Florida Morsani College of Medicine</s1><s2>, Tampa, Florida</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region></placeName></affiliation></author></analytic><series><title level="j" type="main">American journal of physiology. Lung cellular and molecular physiology</title><title level="j" type="abbreviated">Am. j. physiol., Lung cell. mol. physiol.</title><idno type="ISSN">1040-0605</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of physiology. Lung cellular and molecular physiology</title><title level="j" type="abbreviated">Am. j. physiol., Lung cell. mol. physiol.</title><idno type="ISSN">1040-0605</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Activation</term><term>Asthma</term><term>Biological receptor</term><term>Chloroquine</term><term>Desensitization</term><term>Mammalia</term><term>Relaxation</term><term>Respiratory system</term><term>Respiratory tract</term><term>Smooth muscle</term><term>Tachyphylaxis</term><term>Taste</term><term>β2-Adrenergic receptor</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Activation</term><term>Voie respiratoire</term><term>Muscle lisse</term><term>Relaxation</term><term>Récepteur β2-adrénergique</term><term>Tachyphylaxie</term><term>Asthme</term><term>Désensibilisation</term><term>Chloroquine</term><term>Saveur</term><term>Récepteur biologique</term><term>Mammalia</term><term>Appareil respiratoire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca<sup>2+</sup> concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic β-agonists. The β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of β<sub>2</sub>AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of β<sub>2</sub>AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca<sup>2+</sup> concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, β<sub>2</sub>AR desensitization by β-agonist amounted to 92 ± 6.0% (P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic β-agonist exposure culminated in 64 ± 5.7% (P < 0.001) desensitization of β<sub>2</sub>AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic P-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Arkansas</li><li>Floride</li><li>Maryland</li><li>Pennsylvanie</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="An, Steven S" sort="An, Steven S" uniqKey="An S" first="Steven S." last="An">Steven S. An</name></region><name sortKey="Ahn, Kwangmi" sort="Ahn, Kwangmi" uniqKey="Ahn K" first="Kwangmi" last="Ahn">Kwangmi Ahn</name><name sortKey="Koziol White, Cynthia J" sort="Koziol White, Cynthia J" uniqKey="Koziol White C" first="Cynthia J." last="Koziol-White">Cynthia J. Koziol-White</name><name sortKey="Kurten, Richard C" sort="Kurten, Richard C" uniqKey="Kurten R" first="Richard C." last="Kurten">Richard C. Kurten</name><name sortKey="Lee, Danielle Y" sort="Lee, Danielle Y" uniqKey="Lee D" first="Danielle Y." last="Lee">Danielle Y. Lee</name><name sortKey="Liggett, Stephen B" sort="Liggett, Stephen B" uniqKey="Liggett S" first="Stephen B." last="Liggett">Stephen B. Liggett</name><name sortKey="Panettieri, Reynold A Jr" sort="Panettieri, Reynold A Jr" uniqKey="Panettieri R" first="Reynold A. Jr" last="Panettieri">Reynold A. Jr Panettieri</name><name sortKey="Wang, Wayne C H" sort="Wang, Wayne C H" uniqKey="Wang W" first="Wayne C. H." last="Wang">Wayne C. H. Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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