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Circulation Research
Year: 2010  |  Volume: 107  |  Issue: 12  |  Page No.: 1454 - 1459

Muscle-Specific F-Box Only Proteins Facilitate BK Channel {beta}1 Subunit Downregulation in Vascular Smooth Muscle Cells of Diabetes Mellitus

D. m Zhang, T He, Z. S Katusic, H. C Lee and T. Lu    

Abstract: Rationale:

Activity of the large conductance Ca2+-activated K+ (BK) channels is profoundly modulated by its β1 subunit (BK-β1). However, BK-β1 expression is downregulated in diabetic vessels. The ubiquitin–proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β1 downregulation in diabetic vessels is unknown.

Objective:

We hypothesize that UPS facilitates vascular BK-β1 degradation in diabetes.

Methods and Results:

Using patch clamp and molecular biological approaches, we found that BK-β1–mediated channel activation and BK-β1 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-β1 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-β1 expression by 2.16-fold, compared with expression of Flag-hSlo-β1V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-β1 was increased by 1.91-fold, compared with that of hSlo-β1V146A, whereas cotransfection with atrogin-1F (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-β1 protein levels in human CASMCs.

Conclusions:

Downregulation of vascular BK-β1 expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-β1 degradation.

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