{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T08:27:01Z","timestamp":1765960021859,"version":"3.37.3"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T00:00:00Z","timestamp":1546905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,22]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cholera toxin (CT)\u2013induced diarrhea is mediated by cyclic adenosine monophosphate (cAMP)\u2013mediated active Cl\u2013 secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). Although the constitutive activation of adenylyl cyclase (AC) in response to CT is due to adenosine diphosphate ribosylation of the small G protein \u03b1-subunit activating CFTR with consequent secretory diarrhea, the AC isoform(s) involved remain unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated intestinal epithelial cell\u2013specific adenylyl cyclase 6 (AC6) knockout mice to study its role in CT-induced diarrhea.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AC6 messenger RNA levels were the highest of all 9 membrane-bound AC isoforms in mouse intestinal epithelial cells. Intestinal epithelial-specific AC6 knockout mice (AC6loxloxVillinCre) had undetectable AC6 levels in small intestinal and colonic epithelial cells. No significant differences in fluid and food intake, plasma electrolytes, intestinal\/colon anatomy and morphology, or fecal water content were observed between genotypes. Nevertheless, CT-induced fluid accumulation in vivo was completely absent in AC6loxloxVillinCre mice, associated with a lack of forskolin- and CT-induced changes in the short-circuit current (ISC) of the intestinal mucosa, impaired cAMP generation in acutely isolated small intestinal epithelial cells, and significantly impaired apical CFTR levels in response to forskolin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>AC6 is a novel target for the treatment of CT-induced diarrhea.<\/jats:p><\/jats:sec>","DOI":"10.1093\/infdis\/jiz013","type":"journal-article","created":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T15:50:53Z","timestamp":1546962653000},"page":"1719-1728","source":"Crossref","is-referenced-by-count":12,"title":["Adenylyl Cyclase 6 Expression Is Essential for Cholera Toxin\u2013Induced Diarrhea"],"prefix":"10.1093","volume":"220","author":[{"given":"Robert A","family":"Fenton","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sathish K","family":"Murali","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Denmark"},{"name":"University of South Florida, Tampa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Izumi","family":"Kaji","sequence":"additional","affiliation":[{"name":"Greater Los Angeles VA Healthcare System, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasutada","family":"Akiba","sequence":"additional","affiliation":[{"name":"Greater Los Angeles VA Healthcare System, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan D","family":"Kaunitz","sequence":"additional","affiliation":[{"name":"Greater Los Angeles VA Healthcare System, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina B","family":"Kristensen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00f8ren B","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica A","family":"Dominguez Rieg","sequence":"additional","affiliation":[{"name":"University of South Florida, Tampa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6082-662X","authenticated-orcid":false,"given":"Timo","family":"Rieg","sequence":"additional","affiliation":[{"name":"University of South Florida, Tampa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,1,8]]},"reference":[{"key":"2020010309274786000_CIT0001","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1001\/jamapediatrics.2017.0250","article-title":"Child and adolescent health from 1990 to 2015: findings from the Global Burden of Diseases, Injuries, and Risk Factors 2015 study","volume":"171","author":"Kassebaum","year":"2017","journal-title":"JAMA Pediatr"},{"key":"2020010309274786000_CIT0002","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1146\/annurev.physiol.62.1.535","article-title":"Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects","volume":"62","author":"Barrett","year":"2000","journal-title":"Annu Rev Physiol"},{"key":"2020010309274786000_CIT0003","doi-asserted-by":"crossref","first-page":"10094","DOI":"10.1073\/pnas.92.22.10094","article-title":"Transcytosis of cholera toxin subunits across model human intestinal epithelia","volume":"92","author":"Lencer","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020010309274786000_CIT0004","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1172\/JCI200318326","article-title":"Intestinal ion transport and the pathophysiology of diarrhea","volume":"111","author":"Field","year":"2003","journal-title":"J Clin Invest"},{"key":"2020010309274786000_CIT0005","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1126\/science.7524148","article-title":"Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model","volume":"266","author":"Gabriel","year":"1994","journal-title":"Science"},{"key":"2020010309274786000_CIT0006","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1053\/j.gastro.2003.11.005","article-title":"Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor","volume":"126","author":"Thiagarajah","year":"2004","journal-title":"Gastroenterology"},{"key":"2020010309274786000_CIT0007","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1124\/pr.116.013078","article-title":"International union of basic and clinical pharmacology. CI. structures and small molecule modulators of mammalian adenylyl cyclases","volume":"69","author":"Dessauer","year":"2017","journal-title":"Pharmacol Rev"},{"key":"2020010309274786000_CIT0008","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1016\/j.bbadis.2014.08.012","article-title":"Structure, mechanism, and regulation of soluble adenylyl cyclases\u2014similarities and differences to transmembrane adenylyl cyclases","volume":"1842","author":"Steegborn","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"2020010309274786000_CIT0009","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1681\/ASN.2010040409","article-title":"Adenylate cyclase 6 determines cAMP formation and aquaporin-2 phosphorylation and trafficking in inner medulla","volume":"21","author":"Rieg","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"2020010309274786000_CIT0010","doi-asserted-by":"crossref","first-page":"e91042","DOI":"10.1172\/jci.insight.91042","article-title":"Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus","volume":"2","author":"Poulsen","year":"2017","journal-title":"JCI Insight"},{"key":"2020010309274786000_CIT0011","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1681\/ASN.2013101102","article-title":"Renal phosphate wasting in the absence of adenylyl cyclase 6","volume":"25","author":"Fenton","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"2020010309274786000_CIT0012","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ajpath.2012.09.014","article-title":"Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC","volume":"182","author":"Rieg","year":"2013","journal-title":"Am J Pathol"},{"key":"2020010309274786000_CIT0013","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1042\/CS20180060","article-title":"Adenylyl cyclase 6 is required for maintaining acid-base homeostasis","volume":"132","author":"Poulsen","year":"2018","journal-title":"Clin Sci (Lond)"},{"key":"2020010309274786000_CIT0014","doi-asserted-by":"crossref","first-page":"F400","DOI":"10.1152\/ajprenal.2000.279.3.F400","article-title":"Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase","volume":"279","author":"Defer","year":"2000","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020010309274786000_CIT0015","doi-asserted-by":"crossref","first-page":"F78","DOI":"10.1152\/ajprenal.00397.2011","article-title":"Collecting duct-specific knockout of adenylyl cyclase type VI causes a urinary concentration defect in mice","volume":"302","author":"Roos","year":"2012","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020010309274786000_CIT0016","doi-asserted-by":"crossref","first-page":"33275","DOI":"10.1074\/jbc.M204935200","article-title":"Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine","volume":"277","author":"Madison","year":"2002","journal-title":"J Biol Chem"},{"key":"2020010309274786000_CIT0017","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.kint.2017.02.001","article-title":"Renal tubular NHE3 is required in the maintenance of water and sodium chloride homeostasis","volume":"92","author":"Fenton","year":"2017","journal-title":"Kidney Int"},{"key":"2020010309274786000_CIT0018","doi-asserted-by":"crossref","first-page":"2883","DOI":"10.1016\/j.febslet.2010.05.004","article-title":"Impaired water reabsorption in mice deficient in the type VI adenylyl cyclase (AC6)","volume":"584","author":"Chien","year":"2010","journal-title":"FEBS Lett"},{"key":"2020010309274786000_CIT0019","doi-asserted-by":"crossref","first-page":"F1409","DOI":"10.1152\/ajprenal.00129.2015","article-title":"Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3","volume":"308","author":"Fenton","year":"2015","journal-title":"Am J Physiol Renal Physiol"},{"key":"2020010309274786000_CIT0020","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1128\/IAI.43.2.482-486.1984","article-title":"Sealed adult mice: new model for enterotoxin evaluation","volume":"43","author":"Richardson","year":"1984","journal-title":"Infect Immun"},{"key":"2020010309274786000_CIT0021","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1128\/IAI.24.1.19-23.1979","article-title":"Effect of purified Escherichia coli heat-stable enterotoxin on intestinal cyclic nucleotide metabolism and fluid secretion","volume":"24","author":"Giannella","year":"1979","journal-title":"Infect Immun"},{"key":"2020010309274786000_CIT0022","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/labinvest.2015.129","article-title":"Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice","volume":"96","author":"Dominguez Rieg","year":"2016","journal-title":"Lab Invest"},{"key":"2020010309274786000_CIT0023","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/ALN.0b013e318291c2fc","article-title":"Probiotic administration reduces mortality and improves intestinal epithelial homeostasis in experimental sepsis","volume":"119","author":"Khailova","year":"2013","journal-title":"Anesthesiology"},{"key":"2020010309274786000_CIT0024","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1124\/jpet.116.238485","article-title":"Xenin augments duodenal anion secretion via activation of afferent neural pathways","volume":"361","author":"Kaji","year":"2017","journal-title":"J Pharmacol Exp Ther"},{"key":"2020010309274786000_CIT0025","doi-asserted-by":"crossref","first-page":"e292","DOI":"10.21769\/BioProtoc.292","article-title":"Isolation of epithelial cells from mouse gastrointestinal tract for Western blot or RNA analysis","volume":"2","author":"Zeineldin","year":"2012","journal-title":"Bio Protoc"},{"key":"2020010309274786000_CIT0026","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3389\/fnut.2016.00046","article-title":"Characterization of AQPs in mouse, rat, and human colon and their selective regulation by bile acids","volume":"3","author":"Yde","year":"2016","journal-title":"Front Nutr"},{"key":"2020010309274786000_CIT0027","doi-asserted-by":"crossref","first-page":"12981","DOI":"10.1038\/s41598-017-12819-0","article-title":"The thiazide sensitive sodium chloride co-transporter NCC is modulated by site-specific ubiquitylation","volume":"7","author":"Rosenbaek","year":"2017","journal-title":"Sci Rep"},{"key":"2020010309274786000_CIT0028","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1681\/ASN.2017050526","article-title":"CHIP regulates aquaporin-2 quality control and body water homeostasis","volume":"29","author":"Wu","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"2020010309274786000_CIT0029","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00018-016-2388-6","article-title":"Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants","volume":"74","author":"Chin","year":"2017","journal-title":"Cell Mol Life Sci"},{"key":"2020010309274786000_CIT0030","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s11894-014-0376-2","article-title":"Oral rehydration therapy in the second decade of the twenty-first century","volume":"16","author":"Binder","year":"2014","journal-title":"Curr Gastroenterol Rep"},{"key":"2020010309274786000_CIT0031","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nrgastro.2015.111","article-title":"Secretory diarrhoea: mechanisms and emerging therapies","volume":"12","author":"Thiagarajah","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2020010309274786000_CIT0032","doi-asserted-by":"crossref","first-page":"6476","DOI":"10.1074\/jbc.274.10.6476","article-title":"Regulatory sequences of the mouse villin gene that efficiently drive transgenic expression in immature and differentiated epithelial cells of small and large intestines","volume":"274","author":"Pinto","year":"1999","journal-title":"J Biol Chem"},{"key":"2020010309274786000_CIT0033","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1242\/dev.115.3.717","article-title":"Developmental regulation of villin gene expression in the epithelial cell lineages of mouse digestive and urogenital tracts","volume":"115","author":"Maunoury","year":"1992","journal-title":"Development"},{"key":"2020010309274786000_CIT0034","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1042\/bj20030661","article-title":"Fructose modulates GLUT5 mRNA stability in differentiated Caco-2 cells: role of cAMP-signalling pathway and PABP (polyadenylated-binding protein)-interacting protein (Paip) 2","volume":"375","author":"Gouyon","year":"2003","journal-title":"Biochem J"},{"key":"2020010309274786000_CIT0035","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1038\/sj.bjp.0703414","article-title":"The inhibition of cholera toxin-induced 5-HT release by the 5-HT(3) receptor antagonist, granisetron, in the rat","volume":"130","author":"Turvill","year":"2000","journal-title":"Br J Pharmacol"},{"key":"2020010309274786000_CIT0036","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1126\/science.2549637","article-title":"Role of prostaglandins and cAMP in the secretory effects of cholera toxin","volume":"245","author":"Peterson","year":"1989","journal-title":"Science"},{"key":"2020010309274786000_CIT0037","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.tips.2005.02.003","article-title":"New drug targets for cholera therapy","volume":"26","author":"Thiagarajah","year":"2005","journal-title":"Trends Pharmacol Sci"},{"key":"2020010309274786000_CIT0038","doi-asserted-by":"crossref","first-page":"781","DOI":"10.4155\/fmc.13.42","article-title":"Cholera: pathophysiology and emerging therapeutic targets","volume":"5","author":"Muanprasat","year":"2013","journal-title":"Future Med Chem"},{"key":"2020010309274786000_CIT0039","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1096\/fj.201600891R","article-title":"Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor \u00ae-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins","volume":"31","author":"Cil","year":"2017","journal-title":"FASEB J"},{"key":"2020010309274786000_CIT0040","doi-asserted-by":"crossref","first-page":"e0006266","DOI":"10.1371\/journal.pntd.0006266","article-title":"Neutralization of cholera toxin with nanoparticle decoys for treatment of cholera","volume":"12","author":"Das","year":"2018","journal-title":"PLoS Negl Trop Dis"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jid\/article-pdf\/220\/11\/1719\/31700437\/jiz013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jid\/article-pdf\/220\/11\/1719\/31700437\/jiz013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T21:45:12Z","timestamp":1662759912000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/220\/11\/1719\/5280709"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,8]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,1,8]]},"published-print":{"date-parts":[[2019,10,22]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiz013","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"type":"print","value":"0022-1899"},{"type":"electronic","value":"1537-6613"}],"subject":[],"published-other":{"date-parts":[[2019,12,1]]},"published":{"date-parts":[[2019,1,8]]}}}