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Here, we characterized the role of luminal ATP in the regulation of epithelial principal cells (PCs) in the epididymis, an understudied organ that plays crucial roles in male reproduction. We previously showed that ATP secretion by PCs is part of a complex communication system that ensures the establishment of an optimal luminal acidic environment in the epididymis. However, the molecular mechanisms regulating ATP release and the role of ATP-mediated signaling in PCs acidifying functions are not fully understood. In other cell types, pannexin 1 (PANX-1) has been associated with ATP-induced ATP release through the interaction with the purinergic P2X7 receptor. Here, we show that PANX-1 and P2X7 are located in the apical membrane of PCs in the mouse epididymis. Functional analysis using the immortalized epididymal PC cell line (DC2) and the mouse epididymis perfused in vivo showed that (1) PANX-1 and P2X7 participate in ATP release by DC2 cells, together with cystic fibrosis transmembrane conductance regulator (CFTR); (2) several ATP-activated P2Y and P2X purinergic receptors are expressed in DC2 cells; (3) the nonhydrolyzable ATP analog ATP\u03b3S induces a dose-dependent increase in intracellular Ca2+ concentration in DC2 cells, a process that is mainly mediated by P2X7; and (4) perfusion of the epididymal lumen in vivo with ATP\u03b3S induces the internalization of apical sodium-hydrogen exchanger 3 (NHE3) in PCs. Altogether, this study shows that luminal ATP, regulated by CFTR, PANX-1, and P2X7, modulates sodium-proton exchange in PCs in an autocrine manner through activation of purinergic receptor\u2013mediated intracellular calcium signaling.<\/jats:p>","DOI":"10.1093\/function\/zqaf016","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T08:43:23Z","timestamp":1742719403000},"source":"Crossref","is-referenced-by-count":3,"title":["Role of Pannexin 1, P2X7, and CFTR in ATP Release and Autocrine Signaling by Principal Cells of the Epididymis"],"prefix":"10.1152","volume":"6","author":[{"given":"K\u00e9liane","family":"Brochu","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Department of Obstetrics, Gynecology and Reproduction, Centre Hospitalier Universitaire de Qu\u00e9bec\u2014Research Centre, and Centre de Recherche en Reproduction, D\u00e9veloppement et Sant\u00e9 Interg\u00e9n\u00e9rationnelle\u2014Universit\u00e9 Laval , Qu\u00e9bec, QC 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