{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:09:39Z","timestamp":1761919779463,"version":"3.40.4"},"reference-count":72,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2014,2,1]]},"abstract":"<jats:p>Under conditions of high dietary salt intake, prostaglandin E2 (PGE2) production is increased in the collecting duct and promotes urinary sodium chloride (NaCl) excretion; however, the molecular mechanisms by which PGE2 increases NaCl excretion in this context have not been clearly defined. We used the mouse inner medullary collecting duct (mIMCD)-K2 cell line to characterize mechanisms underlying PGE2-regulated NaCl transport. When epithelial Na<jats:sup>+<\/jats:sup>channels were inhibited, PGE2 exclusively stimulated basolateral EP4 receptors to increase short-circuit current ( I<jats:sub>sc<\/jats:sub><jats:sup>PGE2<\/jats:sup>). We found that I<jats:sub>sc<\/jats:sub><jats:sup>PGE2<\/jats:sup>was sensitive to inhibition by H-89 and CFTR-172, indicating that EP4 receptors signal through protein kinase A to induce Cl<jats:sup>\u2212<\/jats:sup>secretion via cystic fibrosis transmembrane conductance regulator (CFTR). Unexpectedly, we also found that I<jats:sub>sc<\/jats:sub><jats:sup>PGE2<\/jats:sup>was sensitive to inhibition by BAPTA-AM (Ca<jats:sup>2+<\/jats:sup>chelator), 2-aminoethoxydiphenyl borate (2-APB) (inositol triphosphate receptor blocker), and flufenamic acid (FFA) [Ca<jats:sup>2+<\/jats:sup>-activated Cl<jats:sup>\u2212<\/jats:sup>channel (CACC) inhibitor], suggesting that EP4 receptors also signal through Ca<jats:sup>2+<\/jats:sup>to induce Cl<jats:sup>\u2212<\/jats:sup>secretion via CACC. Additionally, we observed that PGE2 stimulated an increase in I<jats:sub>sc<\/jats:sub>through crosstalk between cAMP and Ca<jats:sup>2+<\/jats:sup>signaling; BAPTA-AM or 2-APB inhibited a component of I<jats:sub>sc<\/jats:sub><jats:sup>PGE2<\/jats:sup>that was sensitive to CFTR-172 inhibition; H-89 inhibited a component of I<jats:sub>sc<\/jats:sub><jats:sup>PGE2<\/jats:sup>that was sensitive to FFA inhibition. Together, our findings indicate that PGE2 activates basolateral EP4 receptors and signals through both cAMP and Ca<jats:sup>2+<\/jats:sup>to stimulate Cl<jats:sup>\u2212<\/jats:sup>secretion in IMCD-K2 cells. We propose that these signaling pathways, and the crosstalk between them, may provide a concerted mechanism for enhancing urinary NaCl excretion under conditions of high dietary NaCl intake.<\/jats:p>","DOI":"10.1152\/ajpcell.00381.2012","type":"journal-article","created":{"date-parts":[[2013,11,28]],"date-time":"2013-11-28T05:08:13Z","timestamp":1385615293000},"page":"C263-C278","source":"Crossref","is-referenced-by-count":20,"title":["Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells"],"prefix":"10.1152","volume":"306","author":[{"given":"Madhumitha","family":"Rajagopal","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheela V.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paru P.","family":"Kathpalia","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan C.","family":"Pao","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California; and"},{"name":"Veterans Affairs Palo Alto Health Care System, Palo Alto, California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)01436-0"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1833330100"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00152.2001"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.261909"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/0090-6980(76)90043-5"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.t01-1-00325.x"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/0-387-23752-6_10"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1987.253.3.F377"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V718"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00443.2002"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00151.2001"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.90253.2008"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27540"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00564.2007"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024424"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2012.03.005"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00150.2001"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.6.2232"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00032.2007"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.273.2.C747"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00307.2007"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2002.282.1.F1"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(02)02232-4"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.11.7467"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.086124"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1995.268.4.C886"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1997.449"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1124\/mol.110.063933"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000251306.40546.08"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/science.7754369"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0721907.x"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(78)90045-1"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1995.268.2.F347"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00342.2009"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39680"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.3.2.219"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.8.7.566"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00010.2012"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0216112"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.098897"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-159-40364"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207199200"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00247.2012"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.FP0060816"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M408286200"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2004070556"},{"key":"B47","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S0022-3565(25)12931-5","volume":"277","author":"Nuttle LC","year":"1996","journal-title":"J Pharmacol Exp Ther"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1159\/000335765"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.02.097"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-151506"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00426.2004"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00714.2007"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00709.2010"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00062.2012"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.143404"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1985.249.6.F941"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-004-1260-y"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005070727"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00493.x"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.27.3.404"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.1978.235.5.F451"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1152\/ajplegacy.1975.228.2.565"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20051325"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-1248fje"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00201.2007"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1995.269.3.C683"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.272.3.C901"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00165.2002"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2001.280.6.F1019"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1007\/s004240100531"},{"key":"B71","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/S0026-895X(25)10907-3","volume":"37","author":"White MM","year":"1990","journal-title":"Mol Pharmacol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00232.2005"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00381.2012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:07:56Z","timestamp":1746058076000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00381.2012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,1]]},"references-count":72,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014,2,1]]}},"alternative-id":["10.1152\/ajpcell.00381.2012"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00381.2012","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"type":"print","value":"0363-6143"},{"type":"electronic","value":"1522-1563"}],"subject":[],"published":{"date-parts":[[2014,2,1]]}}}