{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:01:40Z","timestamp":1794009700953,"version":"4.8.0"},"reference-count":45,"publisher":"American Physiological Society","issue":"4","funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK52766"],"award-info":[{"award-number":["DK52766"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK66271"],"award-info":[{"award-number":["DK66271"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["P30DK084567"],"award-info":[{"award-number":["P30DK084567"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK106456"],"award-info":[{"award-number":["DK106456"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2018,4,1]]},"abstract":"<jats:p>The SCN5A-encoded voltage-gated mechanosensitive Na<jats:sup>+<\/jats:sup>channel Na<jats:sub>V<\/jats:sub>1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. Na<jats:sub>V<\/jats:sub>1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2\u20133% of patients have SCN5A missense mutations that alter Na<jats:sub>V<\/jats:sub>1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting Na<jats:sub>V<\/jats:sub>1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. Na<jats:sub>V<\/jats:sub>1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated Na<jats:sub>V<\/jats:sub>1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered Na<jats:sub>V<\/jats:sub>1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in Na<jats:sub>V<\/jats:sub>1.5 channels with abnormal voltage-dependent and mechanosensitive function.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY The voltage-gated Na<jats:sup>+<\/jats:sup>channel Na<jats:sub>V<\/jats:sub>1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the Na<jats:sub>V<\/jats:sub>1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant Na<jats:sub>V<\/jats:sub>1.5 channels were loss of function in voltage dependence or mechanosensitivity.<\/jats:p>","DOI":"10.1152\/ajpgi.00016.2017","type":"journal-article","created":{"date-parts":[[2017,11,22]],"date-time":"2017-11-22T17:50:16Z","timestamp":1511373016000},"page":"G494-G503","source":"Crossref","is-referenced-by-count":53,"title":["Irritable bowel syndrome patients have<i>SCN5A<\/i>channelopathies that lead to decreased Na<sub>V<\/sub>1.5 current and mechanosensitivity"],"prefix":"10.1152","volume":"314","author":[{"given":"Peter R.","family":"Strege","sequence":"first","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Mazzone","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl E.","family":"Bernard","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Neshatian","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5311-5993","authenticated-orcid":false,"given":"Simon J.","family":"Gibbons","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri A.","family":"Saito","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa L.","family":"Calvert","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeran A.","family":"Mayer","sequence":"additional","affiliation":[{"name":"Oppenheimer Center for Neurobiology of Stress and Resilience, Division of Digestive Diseases, University of California Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"Oppenheimer Center for Neurobiology of Stress and Resilience, Division of Digestive Diseases, University of California Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Beyder","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianrico","family":"Farrugia","sequence":"additional","affiliation":[{"name":"Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.4065\/73.3.250"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4161\/chan.4.1.10260"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1989.sp017767"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.07.052"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00237.2016"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1177\/1756283X11415892"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12697"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.02.054"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.199034"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.094714"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000052672.97759.36"},{"key":"B12","doi-asserted-by":"crossref","first-page":"G370","DOI":"10.1152\/ajpgi.1996.271.2.G370","volume":"271","author":"Bielefeldt K","year":"1996","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00221.2009"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1974.sp010629"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12173"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.757955"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000032002.22105.7A"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.114.002519"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-313346"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.16.7276"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.30346"},{"key":"B22","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1152\/ajplegacy.1969.217.5.1534","volume":"217","author":"Job DD","year":"1969","journal-title":"Am J Physiol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.863076"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.09.069"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2006.00507.x"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2012.02.029"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000096652.14509.96"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9592.2003.t01-1-00227.x"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.09.084"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1017\/S0033583514000109"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201411304"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.101246"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1991.sp018797"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61554-8"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00051.2015"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2009.44"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.90571.2008"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2006.00743.x"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4081\/cardiogenetics.2012.e11"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80422-5"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00532.2001"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2006.00844.x"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00152.2003"},{"key":"B44","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1101\/gr.1324303","volume":"13","author":"Wong GK","year":"2003","journal-title":"Genome Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/BF00374945"}],"container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpgi.00016.2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T01:53:29Z","timestamp":1659923609000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpgi.00016.2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,1]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,4,1]]}},"alternative-id":["10.1152\/ajpgi.00016.2017"],"URL":"https:\/\/doi.org\/10.1152\/ajpgi.00016.2017","relation":{},"ISSN":["0193-1857","1522-1547"],"issn-type":[{"value":"0193-1857","type":"print"},{"value":"1522-1547","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,1]]}}}