{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:03:18Z","timestamp":1787162598266,"version":"build-2736575974"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2017,5,1]],"date-time":"2017-05-01T00:00:00Z","timestamp":1493596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Diverse classes of ligands have recently been discovered that relax airway smooth muscle (ASM) despite a transient increase in intracellular calcium concentrations ([Ca2+]i). However, the cellular mechanisms are not well understood. Gelsolin is a calcium-activated actin-severing and -capping protein found in many cell types, including ASM cells. Gelsolin also binds to phosphatidylinositol 4,5-bisphosphate, making this substrate less available for phospholipase C\u03b2\u2013mediated hydrolysis to inositol triphosphate and diacylglycerol. We hypothesized that gelsolin plays a critical role in ASM relaxation and mechanistically accounts for relaxation by ligands that transiently increase [Ca2+]i. Isolated tracheal rings from gelsolin knockout (KO) mice showed impaired relaxation to both a \u03b2-agonist and chloroquine, a bitter taste receptor agonist, which relaxes ASM, despite inducing transiently increased [Ca2+]i. A single inhalation of methacholine increased lung resistance to a similar extent in wild-type and gelsolin KO mice, but the subsequent spontaneous relaxation was less in gelsolin KO mice. In ASM cells derived from gelsolin KO mice, serotonin-induced Gq-coupled activation increased both [Ca2+]i and inositol triphosphate synthesis to a greater extent compared to cells from wild-type mice, possibly due to the absence of gelsolin binding to phosphatidylinositol 4,5-bisphosphate. Single-cell analysis showed higher filamentous:globular actin ratio at baseline and slower cytoskeletal remodeling dynamics in gelsolin KO cells. Gelsolin KO ASM cells also showed an attenuated decrease in cell stiffness to chloroquine and flufenamic acid. These findings suggest that gelsolin plays a critical role in ASM relaxation and that activation of gelsolin may contribute to relaxation induced by ligands that relax ASM despite a transient increase in [Ca2+]i.<\/jats:p>","DOI":"10.1165\/rcmb.2016-0292oc","type":"journal-article","created":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T15:54:08Z","timestamp":1490802848000},"page":"628-636","source":"Crossref","is-referenced-by-count":19,"title":["Impaired Relaxation of Airway Smooth Muscle in Mice Lacking the Actin-Binding Protein Gelsolin"],"prefix":"10.1093","volume":"56","author":[{"given":"Maya","family":"Mikami","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Danielsson","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiarra","family":"Joell","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwan Mee","family":"Yong","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Townsend","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Khurana","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Houston, Baylor College of Medicine, Houston, Texas; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven S.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland"},{"name":"Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles W.","family":"Emala","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,5,1]]},"reference":[{"key":"2026021122430383500_bib1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0955-0674(95)80052-2","article-title":"Medical aspects of the actin cytoskeleton","volume":"7","author":"Janmey","year":"1995","journal-title":"Curr Opin Cell Biol"},{"key":"2026021122430383500_bib2","doi-asserted-by":"crossref","first-page":"C792","DOI":"10.1152\/ajpcell.00425.2001","article-title":"Stiffness changes in cultured airway smooth muscle cells","volume":"283","author":"An","year":"2002","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026021122430383500_bib3","doi-asserted-by":"crossref","first-page":"C576","DOI":"10.1152\/ajpcell.00253.2008","article-title":"Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction","volume":"295","author":"Gunst","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026021122430383500_bib4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1513\/pats.200704-048VS","article-title":"Interactions of airway smooth muscle cells with their tissue matrix: implications for contraction","volume":"5","author":"Zhang","year":"2008","journal-title":"Proc Am Thorac Soc"},{"key":"2026021122430383500_bib5","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1006\/scel.1994.1024","article-title":"Regulation of the actin cytoskeleton in living cells","volume":"5","author":"Theriot","year":"1994","journal-title":"Semin Cell Biol"},{"key":"2026021122430383500_bib6","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1067\/mai.2003.128","article-title":"Airway remodeling in asthma: new insights","volume":"111","author":"Davies","year":"2003","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122430383500_bib7","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.jaci.2005.06.011","article-title":"Differences in airway remodeling between subjects with severe and moderate asthma","volume":"116","author":"Pepe","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"2026021122430383500_bib8","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1056\/NEJMp048139","article-title":"Airway smooth muscle in asthma\u2014not just more of the same","volume":"351","author":"Shore","year":"2004","journal-title":"N Engl J Med"},{"key":"2026021122430383500_bib9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0074-7696(07)58001-0","article-title":"Mechanism of depolymerization and severing of actin filaments and its significance in cytoskeletal dynamics","volume":"258","author":"Ono","year":"2007","journal-title":"Int Rev Cytol"},{"key":"2026021122430383500_bib10","doi-asserted-by":"crossref","first-page":"33179","DOI":"10.1074\/jbc.274.47.33179","article-title":"Gelsolin, a multifunctional actin regulatory protein","volume":"274","author":"Sun","year":"1999","journal-title":"J Biol Chem"},{"key":"2026021122430383500_bib11","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/281583a0","article-title":"Control of cytoplasmic actin gel\u2013sol transformation by gelsolin, a calcium-dependent regulatory protein","volume":"281","author":"Yin","year":"1979","journal-title":"Nature"},{"key":"2026021122430383500_bib12","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1016\/S0006-3495(98)77751-3","article-title":"Ca2+ regulation of gelsolin activity: binding and severing of F-actin","volume":"75","author":"Kinosian","year":"1998","journal-title":"Biophys J"},{"key":"2026021122430383500_bib13","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/325362a0","article-title":"Modulation of gelsolin function by phosphatidylinositol 4,5-bisphosphate","volume":"325","author":"Janmey","year":"1987","journal-title":"Nature"},{"key":"2026021122430383500_bib14","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1165\/rcmb.2012-0231OC","article-title":"Effects of ginger and its constituents on airway smooth muscle relaxation and calcium regulation","volume":"48","author":"Townsend","year":"2013","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122430383500_bib15","doi-asserted-by":"crossref","first-page":"L625","DOI":"10.1152\/ajplung.00068.2013","article-title":"Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle","volume":"305","author":"Gallos","year":"2013","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021122430383500_bib16","doi-asserted-by":"crossref","first-page":"L1206","DOI":"10.1152\/ajplung.00287.2007","article-title":"GABAA receptors are expressed and facilitate relaxation in airway smooth muscle","volume":"294","author":"Mizuta","year":"2008","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021122430383500_bib17","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1038\/nm.2237","article-title":"Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction","volume":"16","author":"Deshpande","year":"2010","journal-title":"Nat Med"},{"key":"2026021122430383500_bib18","doi-asserted-by":"crossref","first-page":"e1001501","DOI":"10.1371\/journal.pbio.1001501","article-title":"The cellular and molecular basis of bitter tastant-induced bronchodilation","volume":"11","author":"Zhang","year":"2013","journal-title":"PLoS Biol"},{"key":"2026021122430383500_bib19","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/0092-8674(95)90369-0","article-title":"Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin","volume":"81","author":"Witke","year":"1995","journal-title":"Cell"},{"key":"2026021122430383500_bib20","doi-asserted-by":"crossref","first-page":"L924","DOI":"10.1152\/ajplung.00463.2004","article-title":"Isoproterenol induces actin depolymerization in human airway smooth muscle cells via activation of an Src kinase and GS","volume":"288","author":"Hirshman","year":"2005","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021122430383500_bib21","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1152\/japplphysiol.01129.2003","article-title":"Role of heat shock protein 27 in cytoskeletal remodeling of the airway smooth muscle cell","volume":"96","author":"An","year":"2004","journal-title":"J Appl Physiol (1985)"},{"key":"2026021122430383500_bib22","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.bbrc.2007.01.191","article-title":"Cytoskeleton dynamics: fluctuations within the network","volume":"355","author":"Bursac","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"2026021122430383500_bib23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1165\/rcmb.2005-0453OC","article-title":"Do biophysical properties of the airway smooth muscle in culture predict airway hyperresponsiveness?","volume":"35","author":"An","year":"2006","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021122430383500_bib24","first-page":"L405","article-title":"TNF-\u03b1 upregulates Gi\u03b1 and Gq\u03b1 protein expression and function in human airway smooth muscle cells","volume":"276","author":"Hotta","year":"1999","journal-title":"Am J Physiol"},{"key":"2026021122430383500_bib25","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1513\/pats.200704-051VS","article-title":"Migration of airway smooth muscle cells","volume":"5","author":"Gerthoffer","year":"2008","journal-title":"Proc Am Thorac Soc"},{"key":"2026021122430383500_bib26","first-page":"549252","article-title":"Failure in asthma control: reasons and consequences","volume":"2013","author":"Braido","year":"2013","journal-title":"Scientifica (Cairo)"},{"key":"2026021122430383500_bib27","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S0022-3565(25)12931-5","article-title":"Frequency modulation of acetylcholine-induced oscillations in Ca++ and Ca(++)-activated Cl\u2212 current by cAMP in tracheal smooth muscle","volume":"277","author":"Nuttle","year":"1996","journal-title":"J Pharmacol Exp Ther"},{"key":"2026021122430383500_bib28","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1152\/jappl.1997.82.6.1836","article-title":"Effects of salbutamol on intracellular calcium oscillations in porcine airway smooth muscle","volume":"82","author":"Prakash","year":"1997","journal-title":"J Appl Physiol (1985)"},{"key":"2026021122430383500_bib29","doi-asserted-by":"crossref","first-page":"e0131582","DOI":"10.1371\/journal.pone.0131582","article-title":"Pleiotropic effects of bitter taste receptors on [Ca2+]i mobilization, hyperpolarization, and relaxation of human airway smooth muscle cells","volume":"10","author":"Camoretti-Mercado","year":"2015","journal-title":"PLoS One"},{"key":"2026021122430383500_bib30","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1183\/09031936.00112606","article-title":"Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma","volume":"29","author":"An","year":"2007","journal-title":"Eur Respir J"},{"key":"2026021122430383500_bib31","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1164\/ajrccm\/147.2.405","article-title":"The structure of large and small airways in nonfatal and fatal asthma","volume":"147","author":"Carroll","year":"1993","journal-title":"Am Rev Respir Dis"},{"key":"2026021122430383500_bib32","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1164\/ajrccm\/148.3.720","article-title":"Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma: a 3-D morphometric study","volume":"148","author":"Ebina","year":"1993","journal-title":"Am Rev Respir Dis"},{"key":"2026021122430383500_bib33","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1164\/ajrccm\/148.5.1220","article-title":"Small airways dimensions in asthma and in chronic obstructive pulmonary disease","volume":"148","author":"Kuwano","year":"1993","journal-title":"Am Rev Respir Dis"},{"key":"2026021122430383500_bib34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S1569-9048(03)00148-4","article-title":"Mechanisms of inflammation-mediated airway smooth muscle plasticity and airways remodeling in asthma","volume":"137","author":"Halayko","year":"2003","journal-title":"Respir Physiol Neurobiol"},{"issue":"3 s","key":"2026021122430383500_bib35","doi-asserted-by":"crossref","first-page":"392S","DOI":"10.1378\/chest.123.3_suppl.392S","article-title":"Actin dynamics: a potential integrator of smooth muscle (Dys-)function and contractile apparatus gene expression in asthma: Parker B. Francis lecture","volume":"123","author":"Solway","year":"2003","journal-title":"Chest"},{"key":"2026021122430383500_bib36","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1139\/y05-092","article-title":"Smooth muscle length adaptation and actin filament length: a network model of the cytoskeletal dysregulation","volume":"83","author":"Silveira","year":"2005","journal-title":"Can J Physiol Pharmacol"},{"key":"2026021122430383500_bib37","doi-asserted-by":"crossref","first-page":"8239","DOI":"10.1016\/S0021-9258(18)68469-8","article-title":"Muscle is the major source of plasma gelsolin","volume":"263","author":"Kwiatkowski","year":"1988","journal-title":"J Biol Chem"},{"key":"2026021122430383500_bib38","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/323455a0","article-title":"Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain","volume":"323","author":"Kwiatkowski","year":"1986","journal-title":"Nature"},{"key":"2026021122430383500_bib39","doi-asserted-by":"crossref","first-page":"5271","DOI":"10.1016\/S0021-9258(17)42985-1","article-title":"Structure and biosynthesis of cytoplasmic and secreted variants of gelsolin","volume":"259","author":"Yin","year":"1984","journal-title":"J Biol Chem"},{"key":"2026021122430383500_bib40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1152\/japplphysiol.01074.2002","article-title":"Recombinant plasma gelsolin infusion attenuates burn-induced pulmonary microvascular dysfunction","volume":"96","author":"Rothenbach","year":"2004","journal-title":"J Appl Physiol (1985)"},{"key":"2026021122430383500_bib41","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1126\/science.8310295","article-title":"Reduction in viscosity of cystic fibrosis sputum in vitro by gelsolin","volume":"263","author":"Vasconcellos","year":"1994","journal-title":"Science"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/56\/5\/628\/66831768\/ajrcmb_56_5_628.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/56\/5\/628\/66831768\/ajrcmb_56_5_628.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T03:49:20Z","timestamp":1770868160000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/56\/5\/628\/8467380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,1]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5,1]]},"published-print":{"date-parts":[[2017,5,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2016-0292oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,5]]},"published":{"date-parts":[[2017,5,1]]}}}