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The soluble adenylyl cyclase (sAC) signaling pathway was recently identified as a regulator of melanosomal pH in melanocytes; however, the melanosomal proteins critical for sAC\u2010dependent regulation of melanosomal pH were undefined. We now systematically examine four well\u2010characterized melanosomal membrane proteins to determine whether any of them are required for sAC\u2010dependent regulation of melanosomal pH. We find that OA1, OCA2, and SLC45A2 are dispensable for sAC\u2010dependent regulation of melanosomal pH. In contrast, TPC2 activity is required for sAC\u2010dependent regulation of melanosomal pH and melanin synthesis. In addition, activation of TPC2 by NAADP\u2010AM rescues melanosomal pH alkalinization and reduces melanin synthesis following pharmacologic or genetic inhibition of sAC signaling. These studies establish TPC2 as a critical melanosomal protein for sAC\u2010dependent regulation of melanosomal pH and pigmentation.<\/jats:p>","DOI":"10.1111\/pcmr.13177","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T02:54:27Z","timestamp":1717728867000},"page":"656-666","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Two\u2010pore channel 2 is required for soluble adenylyl cyclase\u2010dependent regulation of melanosomal <scp>pH<\/scp> and melanin synthesis"],"prefix":"10.1111","volume":"37","author":[{"given":"Dalee","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Dermatology Weill Cornell Medical College of Cornell University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuhal","family":"Eraslan","sequence":"additional","affiliation":[{"name":"Department of Dermatology Weill Cornell Medical College of Cornell University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawson","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medical College of Cornell University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isobel","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medical College of Cornell University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewon","family":"You","sequence":"additional","affiliation":[{"name":"Department of Dermatology Weill Cornell Medical College of Cornell University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Grondin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medical College of Cornell University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Vega","sequence":"additional","affiliation":[{"name":"The Ronald O. 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