Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma
β2-adrenergic receptor (β2AR) agonists (β2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation) by phosphorylatio...
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| description | β2-adrenergic receptor (β2AR) agonists (β2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation) by phosphorylation through G-protein coupled receptor kinases (GRKs) which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs) isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie asthma pathophysiology and loss in asthma control. |
| doi_str_mv | 10.1371/journal.pone.0125803 |
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Activation of βARs by β-agonist leads to desensitization (inactivation) by phosphorylation through G-protein coupled receptor kinases (GRKs) which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs) isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie asthma pathophysiology and loss in asthma control.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0125803</identifier><identifier>PMID: 26023787</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Accumulation ; Adrenergic receptors ; Airway management ; Arrestin ; Asthma ; Asthma - metabolism ; Asthma - physiopathology ; Bronchodilators ; Cardiology ; Cell Membrane - metabolism ; Cells, Cultured ; Chronic obstructive pulmonary disease ; Confocal ; Confocal microscopy ; Critical care ; Cyclic AMP - metabolism ; Deactivation ; Defects ; Dephosphorylation ; Desensitization ; Endosomes ; Endosomes - metabolism ; Family medical history ; G protein-coupled receptors ; Homeostasis ; Humans ; Immunoblotting ; Immunoprecipitation ; Inactivation ; Internalization ; Kinases ; Lungs ; Microscopy ; Microscopy, Confocal ; Muscles ; Myocytes, Smooth Muscle - cytology ; Pathology ; Phosphatase ; Phosphorylation ; Proteins ; Receptors ; Receptors, Adrenergic, beta-2 - metabolism ; Reduction ; Respiratory System - cytology ; Respiratory tract ; Smooth muscle ; Studies</subject><ispartof>PloS one, 2015-05, Vol.10 (5), p.e0125803-e0125803</ispartof><rights>2015 Gupta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Gupta et al 2015 Gupta et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-579b73f5c48180b4f5b90781899a873d807b128e650aad47137a97c7f6ada853</citedby><cites>FETCH-LOGICAL-c526t-579b73f5c48180b4f5b90781899a873d807b128e650aad47137a97c7f6ada853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449172/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449172/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26023787$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gupta, Sudhiranjan</contributor><creatorcontrib>Gupta, Manveen K</creatorcontrib><creatorcontrib>Asosingh, Kewal</creatorcontrib><creatorcontrib>Aronica, Mark</creatorcontrib><creatorcontrib>Comhair, Suzy</creatorcontrib><creatorcontrib>Cao, Gaoyuan</creatorcontrib><creatorcontrib>Erzurum, Serpil</creatorcontrib><creatorcontrib>Panettieri, Jr, Reynold A</creatorcontrib><creatorcontrib>Naga Prasad, Sathyamangla V</creatorcontrib><title>Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>β2-adrenergic receptor (β2AR) agonists (β2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. 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However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie asthma pathophysiology and loss in asthma control.</description><subject>Accumulation</subject><subject>Adrenergic receptors</subject><subject>Airway management</subject><subject>Arrestin</subject><subject>Asthma</subject><subject>Asthma - metabolism</subject><subject>Asthma - physiopathology</subject><subject>Bronchodilators</subject><subject>Cardiology</subject><subject>Cell Membrane - metabolism</subject><subject>Cells, Cultured</subject><subject>Chronic obstructive pulmonary disease</subject><subject>Confocal</subject><subject>Confocal microscopy</subject><subject>Critical care</subject><subject>Cyclic AMP - metabolism</subject><subject>Deactivation</subject><subject>Defects</subject><subject>Dephosphorylation</subject><subject>Desensitization</subject><subject>Endosomes</subject><subject>Endosomes - metabolism</subject><subject>Family medical history</subject><subject>G protein-coupled receptors</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunoprecipitation</subject><subject>Inactivation</subject><subject>Internalization</subject><subject>Kinases</subject><subject>Lungs</subject><subject>Microscopy</subject><subject>Microscopy, Confocal</subject><subject>Muscles</subject><subject>Myocytes, Smooth Muscle - cytology</subject><subject>Pathology</subject><subject>Phosphatase</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, Adrenergic, beta-2 - metabolism</subject><subject>Reduction</subject><subject>Respiratory System - cytology</subject><subject>Respiratory tract</subject><subject>Smooth muscle</subject><subject>Studies</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptkt1u0zAUxyMEYmPwBggs7Yabdnb8mRukqhts0tAktnvLcU5al8QudlIoj8WD8EykazptiCsf-fzP73zon2VvCZ4SKsnZKvTRm2a6Dh6mmORcYfosOyYFzScix_T5o_goe5XSCmNOlRAvs6Nc4JxKJY-zn-dQg-3cBtBXSOCT69wv07ngkfPosm-NRzMXf5gtum1D6JboS59sA2gOTZPQxSZ8g4T-_J7Mqgge4sLZAWRh3YWIzrep7r090G5hAxHQLHXL1rzOXtSmSfBmfE-yu08Xd_PLyfXN56v57HpieS66CZdFKWnNLVNE4ZLVvCywHOKiMErSSmFZklyB4NiYisnhNKaQVtbCVEZxepK932PXTUh6vFnSRChGCkYEGRRXe0UVzEqvo2tN3OpgnL7_CHGhTezcsLPGLLe4tkwYaxlAZUpeY0F5bmtiFZcD6-PYrS9bqCz4LprmCfRpxrulXoSNZowVROYD4MMIiOF7D6nTrUt2OLXxEPr7ublkTKldr9N_pP_fju1VNoaUItQPwxCsdz46VOmdj_Too6Hs3eNFHooOxqF_AaeUyFA</recordid><startdate>20150529</startdate><enddate>20150529</enddate><creator>Gupta, Manveen K</creator><creator>Asosingh, Kewal</creator><creator>Aronica, Mark</creator><creator>Comhair, Suzy</creator><creator>Cao, Gaoyuan</creator><creator>Erzurum, Serpil</creator><creator>Panettieri, Jr, Reynold A</creator><creator>Naga Prasad, Sathyamangla V</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150529</creationdate><title>Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma</title><author>Gupta, Manveen K ; Asosingh, Kewal ; Aronica, Mark ; Comhair, Suzy ; Cao, Gaoyuan ; Erzurum, Serpil ; Panettieri, Jr, Reynold A ; Naga Prasad, Sathyamangla V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-579b73f5c48180b4f5b90781899a873d807b128e650aad47137a97c7f6ada853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Accumulation</topic><topic>Adrenergic receptors</topic><topic>Airway management</topic><topic>Arrestin</topic><topic>Asthma</topic><topic>Asthma - metabolism</topic><topic>Asthma - physiopathology</topic><topic>Bronchodilators</topic><topic>Cardiology</topic><topic>Cell Membrane - metabolism</topic><topic>Cells, Cultured</topic><topic>Chronic obstructive pulmonary disease</topic><topic>Confocal</topic><topic>Confocal microscopy</topic><topic>Critical care</topic><topic>Cyclic AMP - metabolism</topic><topic>Deactivation</topic><topic>Defects</topic><topic>Dephosphorylation</topic><topic>Desensitization</topic><topic>Endosomes</topic><topic>Endosomes - metabolism</topic><topic>Family medical history</topic><topic>G protein-coupled receptors</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunoprecipitation</topic><topic>Inactivation</topic><topic>Internalization</topic><topic>Kinases</topic><topic>Lungs</topic><topic>Microscopy</topic><topic>Microscopy, Confocal</topic><topic>Muscles</topic><topic>Myocytes, Smooth Muscle - cytology</topic><topic>Pathology</topic><topic>Phosphatase</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Receptors, Adrenergic, beta-2 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gupta, Manveen K</au><au>Asosingh, Kewal</au><au>Aronica, Mark</au><au>Comhair, Suzy</au><au>Cao, Gaoyuan</au><au>Erzurum, Serpil</au><au>Panettieri, Jr, Reynold A</au><au>Naga Prasad, Sathyamangla V</au><au>Gupta, Sudhiranjan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-05-29</date><risdate>2015</risdate><volume>10</volume><issue>5</issue><spage>e0125803</spage><epage>e0125803</epage><pages>e0125803-e0125803</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>β2-adrenergic receptor (β2AR) agonists (β2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation) by phosphorylation through G-protein coupled receptor kinases (GRKs) which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs) isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie asthma pathophysiology and loss in asthma control.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26023787</pmid><doi>10.1371/journal.pone.0125803</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1684194161 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Accumulation Adrenergic receptors Airway management Arrestin Asthma Asthma - metabolism Asthma - physiopathology Bronchodilators Cardiology Cell Membrane - metabolism Cells, Cultured Chronic obstructive pulmonary disease Confocal Confocal microscopy Critical care Cyclic AMP - metabolism Deactivation Defects Dephosphorylation Desensitization Endosomes Endosomes - metabolism Family medical history G protein-coupled receptors Homeostasis Humans Immunoblotting Immunoprecipitation Inactivation Internalization Kinases Lungs Microscopy Microscopy, Confocal Muscles Myocytes, Smooth Muscle - cytology Pathology Phosphatase Phosphorylation Proteins Receptors Receptors, Adrenergic, beta-2 - metabolism Reduction Respiratory System - cytology Respiratory tract Smooth muscle Studies |
| title | Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T08%3A41%3A55IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Defective%20Resensitization%20in%20Human%20Airway%20Smooth%20Muscle%20Cells%20Evokes%20%CE%B2-Adrenergic%20Receptor%20Dysfunction%20in%20Severe%20Asthma&rft.jtitle=PloS%20one&rft.au=Gupta,%20Manveen%20K&rft.date=2015-05-29&rft.volume=10&rft.issue=5&rft.spage=e0125803&rft.epage=e0125803&rft.pages=e0125803-e0125803&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0125803&rft_dat=%3Cproquest_plos_%3E1685744887%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1684194161&rft_id=info:pmid/26023787&rft_doaj_id=oai_doaj_org_article_042c0fc46acc4eedab5f06352cf1c857&rfr_iscdi=true |