KLI

Roles for H+/K+-ATPase and zinc transporter 3 in cAMP-mediated lysosomal acidification in bafilomycin A1-treated astrocytes

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Abstract
Vacuolar ATPase (v-ATPase) is the main proton pump that acidifies vesicles such as
lysosomes. Disruption in the lysosomal localization of v-ATPase 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-ATPase function may be the
key mechanism underlying the cAMP-mediated lysosomal acidification, it is unknown
whether a mechanism independent of v-ATPase may be contributing to this phenomenon.
In the present study, we modeled v-ATPase dysfunction in brain cells by blocking
lysosomal acidification in cortical astrocytes through treatment with bafilomycin
A1, a selective v-ATPase 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+/K+-
ATPase markedly shifted the lysosomal pH toward more alkaline values in
bafilomycin A1/cAMP-treated astrocytes, suggesting that H+/K+-ATPase may be the
alternative route of proton entry for lysosomal acidification. Furthermore, the cAMPmediated
reversal of lysosomal pH was nullified in the absence of ZnT3 that interacts
with H+/K+-ATPase. Our results suggest that the H+/K+-ATPase/ZnT3 complex is
recruited to lysosomes in a cAMP-dependent manner and functions as an alternative
proton pump for lysosomes when the v-ATPase function is downregulated, thus providing
insight into the potential development of a new class of lysosome-targeted
therapeutics in neurodegenerative diseases.
Author(s)
이희경고재영
Issued Date
2021
Type
Article
Keyword
Adenosine triphosphataseAlzheimer's diseaseAnalysisastrocytesautophagybafilomycin A1cAMPCyclic adenylic acidH+/K+‐ATPaselysosomeMedical researchExperimentalNervous system diseaseszinc transport 3
DOI
10.1002/glia.23952
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7619
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2470024199&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Roles%20for%20H%2B%2FK%2B-ATPase%20and%20zinc%20transporter%203%20in%20cAMP-mediated%20lysosomal%20acidification%20in%20bafilomycin%20A1-treated%20astrocytes&offset=0&pcAvailability=true
Publisher
GLIA
Location
미국
Language
영어
ISSN
0894-1491
Citation Volume
69
Citation Number
5
Citation Start Page
1110
Citation End Page
1125
Appears in Collections:
Medicine > Medicine
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