文章基本信息

标题：Cholesterol efflux to apoA-I in ABCA1-expressing cells is regulated by Ca2+-dependent calcineurin signaling
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作者：Joel Karwatsky ; Loretta Ma ; Fumin Dong 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2010
卷号：51
期号：5
页码：1144-1156
DOI：10.1194/jlr.M003145
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：ATP-binding cassette transporter A1 (ABCA1) is required for the lipidation of apolipoprotein A-I (apoA-I), although molecular mechanisms supporting this process remain poorly defined. In this study, we focused on the role of cytosolic Ca²⁺ and its signaling and found that cytosolic Ca²⁺ was required for cholesterol efflux to apoA-I. Removing extracellular Ca²⁺ or chelating cytosolic Ca²⁺ were equally inhibitory for apoA-I lipidation. We provide evidence that apoA-I induced Ca²⁺ influx from the medium. We further demonstrate that calcineurin activity, the downstream target of Ca²⁺ influx, was essential; inhibition of calcineurin activity by cyclosporine A or FK506 completely abolished apoA-I lipidation. Furthermore, calcineurin inhibition abolished apoA-I binding and diminished JAK2 phosphorylation, an established signaling event for cholesterol efflux to apoA-I. Finally, we demonstrate that neither Ca²⁺ manipulation nor calcineurin inhibition influenced ABCA1's capacity to release microparticles or to remodel the plasma membrane. We conclude that this Ca²⁺-dependent calcineurin/JAK2 pathway is specifically responsible for apoA-I lipidation without directly modifying ABCA1 activity.
关键词：macrophage ; cyclosporine A ; Janus Kinase 2