{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T03:49:28Z","timestamp":1769053768151,"version":"3.49.0"},"reference-count":48,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017M3C7A1028949"],"award-info":[{"award-number":["2017M3C7A1028949"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102016R1E1A1A01941212"],"award-info":[{"award-number":["NRF\u20102016R1E1A1A01941212"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vacuolar ATPase (v\u2010ATPase) is the main proton pump that acidifies vesicles such as lysosomes. Disruption in the lysosomal localization of v\u2010ATPase leads to lysosomal dysfunction, thus contributing to the pathogenesis of lysosomal storage disorders and neurodegenerative diseases such as Alzheimer's disease. Recent studies showed that increases in cyclic AMP (cAMP) levels acidify lysosomes and consequently enhance autophagy flux. Although the upregulation of v\u2010ATPase function may be the key mechanism underlying the cAMP\u2010mediated lysosomal acidification, it is unknown whether a mechanism independent of v\u2010ATPase may be contributing to this phenomenon. In the present study, we modeled v\u2010ATPase dysfunction in brain cells by blocking lysosomal acidification in cortical astrocytes through treatment with bafilomycin A1, a selective v\u2010ATPase inhibitor. We observed that cAMP reversed the pH changes via the activation of protein kinase A; interestingly, cAMP also increased autophagy flux even in the presence of bafilomycin A1, suggesting the presence of an alternative route of proton entry. Notably, pharmacological inhibitors and siRNAs of H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase markedly shifted the lysosomal pH toward more alkaline values in bafilomycin A1\/cAMP\u2010treated astrocytes, suggesting that H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase may be the alternative route of proton entry for lysosomal acidification. Furthermore, the cAMP\u2010mediated reversal of lysosomal pH was nullified in the absence of ZnT3 that interacts with H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase. Our results suggest that the H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase\/ZnT3 complex is recruited to lysosomes in a cAMP\u2010dependent manner and functions as an alternative proton pump for lysosomes when the v\u2010ATPase function is downregulated, thus providing insight into the potential development of a new class of lysosome\u2010targeted therapeutics in neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/glia.23952","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T16:24:09Z","timestamp":1607963049000},"page":"1110-1125","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Roles for H<sup>+<\/sup>\/K<sup>+<\/sup>\u2010<scp>ATPase<\/scp> and zinc transporter 3 in <scp>cAMP<\/scp>\u2010mediated lysosomal acidification in bafilomycin <scp>A1<\/scp>\u2010treated astrocytes"],"prefix":"10.1002","volume":"69","author":[{"given":"Huikyong","family":"Lee","sequence":"first","affiliation":[{"name":"Neural Injury Laboratory, Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center University of Ulsan College of Medicine  Seoul South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4318-495X","authenticated-orcid":false,"given":"Jae\u2010Young","family":"Koh","sequence":"additional","affiliation":[{"name":"Neural Injury Laboratory, Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center University of Ulsan College of Medicine  Seoul South Korea"},{"name":"Department of Neurology, Asan Medical Center University of Ulsan College of Medicine  Seoul South 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