{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:34:53Z","timestamp":1790681693072,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2016,8,2]],"date-time":"2016-08-02T00:00:00Z","timestamp":1470096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,5,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Airway hyper\u2010responsiveness in asthma is driven by excessive contraction of airway smooth muscle cells (ASMCs).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Agonist\u2010induced Ca<jats:sup>2+<\/jats:sup> oscillations underlie this contraction of ASMCs and the magnitude of this contraction is proportional to the Ca<jats:sup>2+<\/jats:sup> oscillation frequency.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Sustained contraction and Ca<jats:sup>2+<\/jats:sup> oscillations require an influx of extracellular Ca<jats:sup>2+<\/jats:sup>, although the mechanisms and pathways mediating this Ca<jats:sup>2+<\/jats:sup> influx during agonist\u2010induced ASMC contraction are not well defined.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>By inhibiting store\u2010operated calcium entry (SOCE) or voltage\u2010gated Ca<jats:sup>2+<\/jats:sup> channels (VGCCs), we show that SOCE, rather than Ca<jats:sup>2+<\/jats:sup> influx via VGCCs, provides the major Ca<jats:sup>2+<\/jats:sup> entry pathway into ASMCs to sustain ASMCs contraction and Ca<jats:sup>2+<\/jats:sup> oscillations.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>SOCE may therefore serve as a potential target for new bronchodilators to reduce airway hyper\u2010responsiveness in asthma.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Asthma is characterized by airway hyper\u2010responsiveness: the excessive contraction of airway smooth muscle. The extent of this airway contraction is proportional to the frequency of Ca<jats:sup>2+<\/jats:sup> oscillations within airway smooth muscle cells (ASMCs). Sustained Ca<jats:sup>2+<\/jats:sup> oscillations require a Ca<jats:sup>2+<\/jats:sup> influx to replenish Ca<jats:sup>2+<\/jats:sup> losses across the plasma membrane. Our previous studies implied store\u2010operated calcium entry (SOCE) as the major pathway for this Ca<jats:sup>2+<\/jats:sup> influx. In the present study, we explore this hypothesis, by examining the effects of SOCE inhibitors (GSK7975A and GSK5498A) as well as L\u2010type voltage\u2010gated Ca<jats:sup>2+<\/jats:sup> channel inhibitors (nifedipine and nimodipine) on airway contraction and Ca<jats:sup>2+<\/jats:sup> oscillations and SOCE\u2010mediated Ca<jats:sup>2+<\/jats:sup> influx in ASMCs within mouse precision\u2010cut lung slices. We found that both GSK7975A and GSK5498A were able to fully relax methacholine\u2010induced airway contraction by abolishing the Ca<jats:sup>2+<\/jats:sup> oscillations, in a manner similar to that observed in zero extracellular Ca<jats:sup>2+<\/jats:sup> ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>e<\/jats:sub>). In addition, GSK7975A and GSK5498A inhibited increases in intracellular Ca<jats:sup>2+<\/jats:sup> ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) in ASMCs with depleted Ca<jats:sup>2+<\/jats:sup>\u2010stores in response to increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>e<\/jats:sub>, demonstrating a response consistent with the inhibition of SOCE. However, GSK7975A and GSK5498A did not reduce Ca<jats:sup>2+<\/jats:sup> release via IP<jats:sub>3<\/jats:sub> receptors stimulated with IP<jats:sub>3<\/jats:sub> released from caged\u2010IP<jats:sub>3<\/jats:sub>. By contrast, nifedipine and nimodipine only partially reduced airway contraction, Ca<jats:sup>2+<\/jats:sup> oscillation frequency and SOCE\u2010mediated Ca<jats:sup>2+<\/jats:sup> influx. These data suggest that SOCE is the major Ca<jats:sup>2+<\/jats:sup> influx pathway for ASMCs with respect to sustaining agonist\u2010induced airway contraction and the underlying Ca<jats:sup>2+<\/jats:sup> oscillations. The mechanisms of SOCE may therefore form novel targets for new bronchodilators.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp272694","type":"journal-article","created":{"date-parts":[[2016,7,11]],"date-time":"2016-07-11T09:38:20Z","timestamp":1468229900000},"page":"3203-3218","source":"Crossref","is-referenced-by-count":57,"title":["Store\u2010operated calcium entry is required for sustained contraction and Ca<sup>2+<\/sup> oscillations of airway smooth muscle"],"prefix":"10.1113","volume":"595","author":[{"given":"Jun","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Microbiology and Physiological Systems University of Massachusetts Medical School  Worcester MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Sanderson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Physiological Systems University of Massachusetts Medical School  Worcester MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,8,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00112606"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.01.070"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00317.2003"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2013.10.006"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-7-34"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00494.2005"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.90288.2008"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1155"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0386OC"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069598"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2006-0096OC"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00092.2005"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2012.11.005"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M606541200"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04702"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2013.09.060"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00035.2006"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201504-0763PP"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.4161\/chan.25292"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00452.2001"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1997.272.4.L659"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05637"},{"key":"e_1_2_6_25_1","first-page":"407","article-title":"Intercellular calcium signaling and flash photolysis of caged compounds. 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