{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:13:36Z","timestamp":1791278016436,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2012,12,18]],"date-time":"2012-12-18T00:00:00Z","timestamp":1355788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,1]]},"abstract":"Background And Purpose<\/jats:title>Ca2+<\/jats:sup>\u2010dependent C<\/jats:styled-content>l\u2212<\/jats:sup> secretion (CaCC<\/jats:styled-content>) in airways and other tissues is due to activation of the C<\/jats:styled-content>l\u2212<\/jats:sup> channel TMEM16A<\/jats:styled-content> (anoctamin 1). Earlier studies suggested that C<\/jats:styled-content>a2+<\/jats:sup>\u2010activated C<\/jats:styled-content>l\u2212<\/jats:sup> channels are regulated by membrane lipid inositol phosphates, and that 1\u2010O<\/jats:styled-content>\u2010octyl\u20102\u2010O<\/jats:styled-content>\u2010butyryl\u2010myo\u2010inositol 3,4,5,6\u2010tetrakisphosphate octakis(propionoxymethyl) ester (INO<\/jats:styled-content>\u20104995) augments CaCC<\/jats:styled-content>. Here we examined whether TMEM16A<\/jats:styled-content> is the target for INO<\/jats:styled-content>\u20104995 and if the channel is regulated by inositol phosphates.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>The effects of INO<\/jats:styled-content>\u20104995 on CaCC<\/jats:styled-content> were examined in overexpressing HEK<\/jats:styled-content>293, colonic and primary airway epithelial cells as well as X<\/jats:styled-content>enopus<\/jats:italic> oocytes. We used patch clamping, double electrode voltage clamp and U<\/jats:styled-content>ssing chamber techniques.<\/jats:p><\/jats:sec>Key Results<\/jats:title>We found that INO<\/jats:styled-content>\u20104995 directly activates a TMEM16A<\/jats:styled-content> whole cell conductance of 6.1 \u00b1 0.9\u2009nS pF\u20131<\/jats:sup><\/jats:styled-content> in overexpressing cells. The tetrakisphosphates I<\/jats:styled-content>ns(3,4,5,6)P<\/jats:styled-content>4<\/jats:sub> or I<\/jats:styled-content>ns(1,3,4,5)P<\/jats:styled-content>4<\/jats:sub> and enzymes controlling levels of I<\/jats:styled-content>nsP<\/jats:styled-content>4<\/jats:sub> or PIP<\/jats:styled-content>2<\/jats:sub> and PIP<\/jats:styled-content>3<\/jats:sub> had no effects on the magnitude or kinetics of TMEM16A<\/jats:styled-content> currents. In contrast in X<\/jats:styled-content>enopus<\/jats:italic> oocytes, human airways and colonic cells, which all express TMEM16A<\/jats:styled-content> endogenously, C<\/jats:styled-content>l\u2212<\/jats:sup> currents were not acutely activated by INO<\/jats:styled-content>\u20104995. However incubation with INO<\/jats:styled-content>\u20104995 augmented 1.6\u2010 to 4\u2010fold TMEM16A<\/jats:styled-content>\u2010dependent C<\/jats:styled-content>l\u2212<\/jats:sup> currents activated by ionomycin or ATP<\/jats:styled-content>, while intracellular C<\/jats:styled-content>a2+<\/jats:sup> signals were not affected. The potentiating effect of INO<\/jats:styled-content>\u20104995 on transient ATP<\/jats:styled-content>\u2010activated TMEM16A<\/jats:styled-content>\u2010currents in cystic fibrosis (CF)<\/jats:styled-content> airways was twice of that observed in non\u2010CF<\/jats:styled-content> airways.<\/jats:p><\/jats:sec>Conclusions And Implications<\/jats:title>These data indicate that TMEM16A<\/jats:styled-content> is the target for INO<\/jats:styled-content>\u20104995, although the mode of action appears different for overexpressed and endogenous channels. INO<\/jats:styled-content>\u20104995 may be useful for the treatment of CF<\/jats:styled-content> lung disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1476-5381.2012.02193.x","type":"journal-article","created":{"date-parts":[[2012,9,4]],"date-time":"2012-09-04T11:09:12Z","timestamp":1346756952000},"page":"253-265","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Control of TMEM16A<\/scp> by INO<\/scp>\u20104995 and other inositolphosphates"],"prefix":"10.1111","volume":"168","author":[{"given":"Yuemin","family":"Tian","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Physiologie Universit\u00e4t Regensburg Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Physiologie Universit\u00e4t Regensburg Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Podchanart","family":"Wanitchakool","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Physiologie Universit\u00e4t Regensburg Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patthara","family":"Kongsuphol","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Physiologie Universit\u00e4t Regensburg Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Sousa","sequence":"additional","affiliation":[{"name":"Faculty of Sciences BioFIG \u2013 Centre for Biodiversity Functional and Integrative Genomics University of Lisboa Lisboa Portugal"},{"name":"Department of Genetics National Institute of Health Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Uliyakina","sequence":"additional","affiliation":[{"name":"Faculty of Sciences BioFIG \u2013 Centre for Biodiversity Functional and Integrative Genomics University of Lisboa Lisboa Portugal"},{"name":"Department of Genetics National Institute of Health Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Palma","sequence":"additional","affiliation":[{"name":"Faculty of Sciences BioFIG \u2013 Centre for Biodiversity Functional and Integrative Genomics University of Lisboa Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Faria","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Physiologie Universit\u00e4t Regensburg Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis E","family":"Traynor\u2010Kaplan","sequence":"additional","affiliation":[{"name":"ISM Therapeutics Seattle WA USA"},{"name":"Division of Gastroenterology Department of Medicine University of Washington Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 I","family":"Fragata","sequence":"additional","affiliation":[{"name":"Department Cardio\u2010Thoracic Surgery Hospital de Santa Marta Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarida D","family":"Amaral","sequence":"additional","affiliation":[{"name":"Faculty of Sciences BioFIG \u2013 Centre for Biodiversity Functional and Integrative Genomics University of Lisboa Lisboa Portugal"},{"name":"Department of Genetics National Institute of Health Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Kunzelmann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Physiologie Universit\u00e4t Regensburg Regensburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,12,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.010074"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/10715769900300461"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504347200"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2867-6-7"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1163518"},{"key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"26906","DOI":"10.1016\/S0021-9258(19)61460-2","article-title":"myo\u2010inositol 3,4,5,6\u2010tetrakisphosphate inhibits an apical calcium\u2010activated chloride conductance in polarized monolayers of a cystic fibrosis cell line","volume":"275","author":"Carew MA","year":"2000","journal-title":"J Biol Chem"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703121200"},{"key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"32464","DOI":"10.1016\/S0021-9258(18)31658-2","article-title":"Annexin IV inhibits calmodulin\u2010dependent protein kinase II\u2010activated chloride conductance. 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