{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:37:18Z","timestamp":1781102238497,"version":"3.54.1"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"49","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,12,6]]},"abstract":"<jats:p>\n                    In asthma and chronic obstructive pulmonary disease, activation of G\n                    <jats:sub>q<\/jats:sub>\n                    -protein\u2013coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)\/long-acting \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid\/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G\n                    <jats:sub>q<\/jats:sub>\n                    signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally,\n                    <jats:italic>Rgs2<\/jats:italic>\n                    -deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)\/LABA combinations in obstructive airways diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1110226108","type":"journal-article","created":{"date-parts":[[2011,11,12]],"date-time":"2011-11-12T01:03:09Z","timestamp":1321059789000},"page":"19713-19718","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":80,"title":["\u03b2\n                    <sub>2<\/sub>\n                    -Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids"],"prefix":"10.1073","volume":"108","author":[{"given":"Neil S.","family":"Holden","sequence":"first","affiliation":[{"name":"Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Bell","sequence":"additional","affiliation":[{"name":"Respiratory Inflammation and Autoimmunity Department, MedImmune, Cambridge CB21 6GH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher F.","family":"Rider","sequence":"additional","affiliation":[{"name":"Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"King","sequence":"additional","affiliation":[{"name":"Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David D.","family":"Gaunt","sequence":"additional","affiliation":[{"name":"Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Leigh","sequence":"additional","affiliation":[{"name":"Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm","family":"Johnson","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline Research and Development, Uxbridge, Middlesex UB6 0HE, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Siderovski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott P.","family":"Heximer","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Giembycz","sequence":"additional","affiliation":[{"name":"Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Newton","sequence":"additional","affiliation":[{"name":"Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,11,11]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00138707"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200703-456SO"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.320.7246.1368"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.11.003"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2254"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-7-73"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2009.129296"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.06.00112605"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.1.51"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(04)90005-5"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.024711"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.040121"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.19.6706-6718.2002"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.24.9774"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.025841"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.060020"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.006486"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00046.2008"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00499.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a021780"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.220414397"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-11-82"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707627"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.prrv.2009.10.001"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0900544"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(04)89005-0"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M312407200"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.005827"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm958"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200315598"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.08.061"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09564"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00277.x"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407008101"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801551105"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.57.3.460"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(02)00698-1"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.212480"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1990.tb14666.x"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb13439.x"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2005.04.009"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.028381"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210663200"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1110226108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T20:31:23Z","timestamp":1649795483000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1110226108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,11,11]]},"references-count":43,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2011,12,6]]}},"alternative-id":["10.1073\/pnas.1110226108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1110226108","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.13408991.14779105","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.13408991.792203015","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,11,11]]},"assertion":[{"value":"2011-11-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}