Regulation of large conductance Ca2+-activated K+ (BK) Channel β1 subunit expression by muscle RING finger protein 1 in diabetic vessels

Fu Yi, Huan Wang, Qiang Chai, Xiaoli Wang, Win Kuang Shen, Monte S. Willis, Hon Chi Lee, Tong Lu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

The large conductance Ca2+-activated K+ (BK) channel, expressed abundantly in vascular smooth muscle cells (SMCs), is a key determinant of vascular tone. BK channel activity is tightly regulated by its accessory β1 subunit (BK- β1). However, BK channel function is impaired in diabetic vessels by increased ubiquitin/proteasome-dependent BK- β1 protein degradation. Muscle RING finger protein 1 (MuRF1), a muscle-specific ubiquitin ligase, is implicated in many cardiac and skeletal muscle diseases. However, the role of MuRF1 in the regulation of vascular BK channel and coronary function has not been examined. In this study, we hypothesized that MuRF1 participated in BK- β1 proteolysis, leading to the down-regulation of BK channel activation and impaired coronary function in diabetes. Combining patch clamp and molecular biological approaches, we found that MuRF1 expression was enhanced, accompanied by reduced BK- β1 expression, in high glucose-cultured human coronary SMCs and in diabetic vessels. Knockdown of MuRF1 by siRNA in cultured human SMCs attenuated BK- β1 ubiquitination and increased BK- β1 expression, whereas adenoviral expression of MuRF1 in mouse coronary arteries reduced BK- β1 expression and diminished BK channel-mediated vasodilation. Physical interaction between the N terminus of BK- β1 and the coiled-coil domain ofMuRF1was demonstrated by pulldown assay. Moreover, MuRF1 expression was regulated by NF-κB. Most importantly, pharmacological inhibition of proteasome and NF-κB activities preserved BK- β1 expression and BK-channel-mediated coronary vasodilation in diabetic mice. Hence, our results provide the first evidence that the up-regulation of NF-κB-dependent MuRF1 expression is a novel mechanism that leads to BK channelopathy and vasculopathy in diabetes.

Original languageEnglish (US)
Pages (from-to)10853-10864
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number15
DOIs
StatePublished - Apr 11 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Regulation of large conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK) Channel β1 subunit expression by muscle RING finger protein 1 in diabetic vessels'. Together they form a unique fingerprint.

Cite this