Role of Hsp90 in biogenesis of the β-cell ATP-sensitive potassium channel complex

Fei Fei Yan, Emily B. Pratt, Pei Chun Chen, Fang Wang, William R. Skach, Larry L. David, Show Ling Shyng

研究成果: Article同行評審

34 引文 斯高帕斯(Scopus)

摘要

The pancreatic β-cell ATP-sensitive potassium (KATP) channel is a multimeric protein complex composed of four inwardly rectifying potassium channel (Kir6.2) and four sulfonylurea receptor 1 (SUR1) subunits. K ATP channels play a key role in glucose-stimulated insulin secretion by linking glucose metabolism to membrane excitability. Many SUR1 and Kir6.2 mutations reduce channel function by disrupting channel biogenesis and processing, resulting in insulin secretion disease. To better understand the mechanisms governing KATP channel biogenesis, a proteomics approach was used to identify chaperone proteins associated with KATP channels. We report that chaperone proteins heat-shock protein (Hsp)90, heat-shock cognate protein (Hsc)70, and Hsp40 are associated with β-cell KATP channels. Pharmacologic inhibition of Hsp90 function by geldanamycin reduces, whereas overexpression of Hsp90 increases surface expression of wild-type KATP channels. Coimmunoprecipitation data indicate that channel association with the Hsp90 complex is mediated through SUR1. Accordingly, manipulation of Hsp90 protein expression or function has significant effects on the biogenesis efficiency of SUR1, but not Kir6.2, expressed alone. Interestingly, overexpression of Hsp90 selectively improved surface expression of mutant channels harboring a subset of disease-causing SUR1 processing mutations. Our study demonstrates that Hsp90 regulates biogenesis efficiency of heteromeric KATP channels via SUR, thereby affecting functional expression of the channel in β-cell membrane.

原文English
頁(從 - 到)1945-1954
頁數10
期刊Molecular Biology of the Cell
21
發行號12
DOIs
出版狀態Published - 2010 六月 15

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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