{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:51:06Z","timestamp":1792025466321,"version":"4.4.0"},"reference-count":30,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T00:00:00Z","timestamp":1623110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DK126070"],"award-info":[{"award-number":["DK126070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DK072517"],"award-info":[{"award-number":["DK072517"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"crossref","award":["VERKMA18G0"],"award-info":[{"award-number":["VERKMA18G0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,8]]},"abstract":"<jats:p>\n                    SLC26A6 (also known as putative anion transporter 1 [PAT1]) is a Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    \/HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2013<\/jats:sup>\n                    exchanger expressed at the luminal membrane of enterocytes where it facilitates intestinal Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    and fluid absorption. Here, high-throughput screening of 50,000 synthetic small molecules in cells expressing PAT1 and a halide-sensing fluorescent protein identified several classes of inhibitors. The most potent compound, the pyrazolo-pyrido-pyrimidinone PAT1\n                    <jats:sub>inh<\/jats:sub>\n                    -B01, fully inhibited PAT1-mediated anion exchange (IC\n                    <jats:sub>50<\/jats:sub>\n                    ~350 nM), without inhibition of the related intestinal transporter SLC26A3 (also known as DRA). In closed midjejunal loops in mice, PAT1\n                    <jats:sub>inh<\/jats:sub>\n                    -B01 inhibited fluid absorption by 50%, which increased to &gt;90% when coadministered with DRA inhibitor DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A270. In ileal loops, PAT1\n                    <jats:sub>inh<\/jats:sub>\n                    -B01 blocked fluid absorption by &gt;80%, whereas DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A270 was without effect. In colonic loops, PAT1\n                    <jats:sub>inh<\/jats:sub>\n                    -B01 was without effect, whereas DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A270 completely blocked fluid absorption. In a loperamide constipation model, coadministration of PAT1\n                    <jats:sub>inh<\/jats:sub>\n                    -B01 with DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A270 increased stool output compared with DRA\n                    <jats:sub>inh<\/jats:sub>\n                    -A270 alone. These results provide functional evidence for complementary and region-specific roles of PAT1 and DRA in intestinal fluid absorption, with PAT1 as the predominant anion exchanger in mouse ileum. We believe that PAT1\n                    <jats:sub>inh<\/jats:sub>\n                    -B01 is a novel tool to study intestinal ion and fluid transport and perhaps a drug candidate for small intestinal hyposecretory disorders such as cystic fibrosis\u2013related meconium ileus and distal intestinal obstruction syndrome.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.147699","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T09:01:05Z","timestamp":1623747665000},"source":"Crossref","is-referenced-by-count":19,"title":["SLC26A6-selective inhibitor identified in a small-molecule screen blocks fluid absorption in small intestine"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5178-0199","authenticated-orcid":true,"given":"Onur","family":"Cil","sequence":"first","affiliation":[{"name":"Department of Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Haggie","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9795-4705","authenticated-orcid":true,"given":"Joseph-Anthony Tapia","family":"Tan","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber A.","family":"Rivera","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5054-0078","authenticated-orcid":true,"given":"Alan S.","family":"Verkman","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"issue":"6","key":"B1","doi-asserted-by":"crossref","first-page":"G1385","DOI":"10.1152\/ajpgi.2001.281.6.G1385","article-title":"Loss of the NHE2 Na(+)\/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice","volume":"281","author":"Ledoussal","year":"2005","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"7","key":"B2","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1080\/17425255.2020.1767067","article-title":"An update on efficacy and safety considerations for the latest drugs used to treat irritable bowel syndrome","volume":"16","author":"Mousavi","year":"2020","journal-title":"Expert Opin Drug Metab 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enterotoxins","volume":"31","author":"Cil","year":"2016","journal-title":"FASEB J"},{"key":"B30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.trsl.2016.10.003","article-title":"Phenylquinoxalinone CFTR activator as potential prosecretory therapy for constipation","volume":"182","author":"Cil","year":"2017","journal-title":"Transl Res"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/147699\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:31:03Z","timestamp":1779150663000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/147699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,8]]},"references-count":30,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6,8]]},"published-print":{"date-parts":[[2021,6,8]]}},"alternative-id":["10.1172\/jci.insight.147699"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.147699","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,8]]},"article-number":"e147699"}}