(5R)-6, 6-Dibromopenicillanate와 Hydroxy aldehydes의 축합반응에 관한 연구

학위논문(석사)--서울大學校 大學院 :化學科 有機化學專攻,1997.Maste

Application of HSPF Model for fecal coliform simulation in rural watersheds

학위논문(석사) --서울대학교 대학원 :생태조경.지역시스템공학부(지역시스템공학전공),2007.Maste

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

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