{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:40:14Z","timestamp":1783489214806,"version":"3.55.0"},"reference-count":62,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,2,28]],"date-time":"2019-02-28T00:00:00Z","timestamp":1551312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HD040793"],"award-info":[{"award-number":["HD040793"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK097124"],"award-info":[{"award-number":["DK097124"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK042956"],"award-info":[{"award-number":["DK042956"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012756","name":"Lalor Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012756","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In the epididymis, elaborate communication networks between epithelial cells are important with respect to establishing an optimal acidic luminal environment for the maturation and storage of spermatozoa, which is essential for male fertility.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Proton secretion by epididymal clear cells is achieved via the proton pumping V\u2010ATPase located in their apical membrane.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the present study, we dissect the molecular mechanisms by which clear cells respond to luminal ATP and adenosine to modulate their acidifying activity via the adenosine receptor ADORA2B and the pH\u2010sensitive ATP receptor P2X4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We demonstrate that the hydrolysis of ATP to produce adenosine by ectonucleotidases plays a key role in V\u2010ATPase\u2010dependent proton secretion, and is part of a feedback loop that ensures acidification of the luminal compartment<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results help us better understand how professional proton\u2010secreting cells respond to extracellular cues to modulate their functions, and how they communicate with neighbouring cells.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Cell\u2013cell cross\u2010talk is crucial for the dynamic function of epithelia, although how epithelial cells detect and respond to variations in extracellular stimuli to modulate their environment remains incompletely understood. In the present study, we used the epididymis as a model system to investigate epithelial cell regulation by luminal factors. In the epididymis, elaborate communication networks between the different epithelial cell types are important for establishing an optimal acidic luminal environment for the maturation and storage of spermatozoa. In particular, clear cells (CCs) secrete protons into the lumen via the proton pumping V\u2010ATPase located in their apical membrane, a process that is activated by luminal alkalinization. However, how CCs detect luminal pH variations to modulate their function remains uncharacterized. Purinergic regulation of epithelial transport is modulated by extracellular pH in other tissues. In the present study, functional analysis of the mouse cauda epididymis perfused <jats:italic>in vivo<\/jats:italic> showed that luminal ATP and adenosine modulate the acidifying activity of CCs via the purinergic ADORA2B and P2X4 receptors, and that luminal adenosine content is itself regulated by luminal pH. Altogether, our observations illustrate mechanisms by which CCs are activated by pH sensitive P2X4 receptor and ectonucleotidases, providing a feedback mechanism for the maintenance of luminal pH. These novel mechanisms by which professional proton\u2010secreting cells respond to extracellular cues to modulate their functions, as well as how they communicate with neighbouring cells, might be translatable to other acidifying epithelia.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp277565","type":"journal-article","created":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T11:02:18Z","timestamp":1549969338000},"page":"1957-1973","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Unravelling purinergic regulation in the epididymis: activation of V\u2010ATPase\u2010dependent acidification by luminal ATP and adenosine"],"prefix":"10.1113","volume":"597","author":[{"given":"Maria A.","family":"Battistone","sequence":"first","affiliation":[{"name":"Program in Membrane Biology, Center for System Biology, Nephrology Division, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston MA 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