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    Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion

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    Authors
    Fonseca, Sonya G.
    Urano, Fumihiko
    Weir, Gordon C.
    Gromada, Jesper
    Burcin, Mark
    UMass Chan Affiliations
    Program in Gene Function and Expression
    Document Type
    Journal Article
    Publication Date
    2012-09-16
    Keywords
    Calmodulin-Binding Proteins
    Membrane Proteins
    Adenylate Cyclase
    Cell Membrane
    Insulin
    Biochemistry, Biophysics, and Structural Biology
    Genetics and Genomics
    
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    Link to Full Text
    http://dx.doi.org/10.1038/ncb2578
    Abstract
    Endoplasmic reticulum (ER) stress causes pancreatic beta-cell dysfunction and contributes to beta-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in beta-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the beta-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for beta-cell dysfunction and progression of type 2 diabetes.
    Source
    Nat Cell Biol. 2012 Sep 16. doi: 10.1038/ncb2578. Link to article on publisher's site
    DOI
    10.1038/ncb2578
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43996
    PubMed ID
    22983116
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1038/ncb2578
    Scopus Count
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