| Muscle-specific f-box only proteins facilitate bk channel β(1) subunit downregulation in vascular smooth muscle cells of diabetes mellitus. | |
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MedLine Citation:
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PMID: 20966391 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: activity of the large conductance Ca(2+)-activated K(+) (BK) channels is profoundly modulated by its β(1) subunit (BK-β(1)). However, BK-β(1) expression is downregulated in diabetic vessels. The ubiquitin-proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β(1) downregulation in diabetic vessels is unknown. OBJECTIVE: we hypothesize that UPS facilitates vascular BK-β(1) degradation in diabetes. METHODS AND RESULTS: using patch clamp and molecular biological approaches, we found that BK-β(1)-mediated channel activation and BK-β(1) protein expression were reduced in aortas of streptozotocin-induced diabetic rats and in human coronary arterial smooth muscle cells (CASMCs) cultured in high glucose. This was accompanied by upregulation of F-box only protein (FBXO)-9 and FBXO-32 (atrogin-1), the key components of the Skp1-Cullin-F-box (SCF) type ubiquitin ligase complex. BK-β(1) expression was suppressed by the FBXO activator doxorubicin but enhanced by FBXO-9 small interfering RNA or by the proteasome inhibitor MG-132. Cotransfection of atrogin-1 in HEK293 cells significantly reduced Flag-hSlo-β(1) expression by 2.16-fold, compared with expression of Flag-hSlo-β(1)V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-β(1) was increased by 1.91-fold, compared with that of hSlo-β(1)V146A, whereas cotransfection with atrogin-1ΔF (a nonfunctional mutant without the F-box motif) had no effect. Moreover, inhibition of Akt signaling attenuated the phosphorylation of forkhead box O transcription factor (FOXO)-3a and enhanced atrogin-1 expression, which in turn suppressed BK-β(1) protein levels in human CASMCs. CONCLUSIONS: downregulation of vascular BK-β(1) expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-β(1) degradation. |
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Authors:
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Dai-Min Zhang; Tongrong He; Zvonimir S Katusic; Hon-Chi Lee; Tong Lu |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-21 |
Journal Detail:
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Title: Circulation research Volume: 107 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-14 Completed Date: 2011-01-24 Revised Date: 2012-04-11 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1454-9 Citation Subset: IM |
Affiliation:
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Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cells, Cultured Diabetes Mellitus / metabolism* Down-Regulation* F-Box Proteins / physiology* Forkhead Transcription Factors / physiology Glucose Humans Large-Conductance Calcium-Activated Potassium Channels / metabolism* Muscle, Smooth, Vascular / pathology* Myocytes, Smooth Muscle / metabolism* Proteasome Endopeptidase Complex / metabolism Protein Stability Protein Subunits / metabolism Ubiquitin / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL080118/HL/NHLBI NIH HHS; HL74180/HL/NHLBI NIH HHS; HL91867/HL/NHLBI NIH HHS; R01 HL074180-04/HL/NHLBI NIH HHS; R01 HL074180-08/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/F-Box Proteins; 0/FOXO3 protein, human; 0/Forkhead Transcription Factors; 0/Large-Conductance Calcium-Activated Potassium Channels; 0/Protein Subunits; 0/Ubiquitin; 50-99-7/Glucose; EC 3.4.25.1/Proteasome Endopeptidase Complex |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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