BK Channel Dysfunction in Diabetic Coronary Artery: Role of the E3 Ubiquitin Ligases

Abstract

Diabetic coronary arterial disease is a leading cause of morbidity and mortality in diabetic patients. The impaired function of large-conductance calcium-activated potassium channels (BK channels) is involved in diabetic coronary arterial disease. Many studies have indicated that the reduced BK channel expression in diabetic coronary artery is attributed to ubiquitin-mediated protein degradation by the ubiquitin-proteasome system. This review focuses on the influence and the mechanisms of BK channel regulation by E3 ubiquitin ligases in diabetic coronary arterial disease. Thus, BK channels regulated by E3 ubiquitin ligase may play a pivotal role in the coronary pathogenesis of diabetic mellitus and, as such, is a potentially attractive target for therapeutic intervention.

Keywords: BK channel; E3 ubiquitin ligase; coronary artery; diabetes mellitus; ubiquitin–proteasome system.

FIGURE 1

A schematic figure of the ubiquitin proteasome system. Initially, a single free ubiquitin was activated by E1 in an ATP-dependent manner and then the activated monoubiquitin molecule is transferred to a cysteine residue of the E2 enzyme, which is subsequently recruited into the E3 ligases. Working with a specific E3, E2 transferred one or more ubiquitin moieties sequentially to form ubiquitin chains to the substrate protein. Finally, the proteasome system can target the ubiquitinated substrate protein for degradation.

FIGURE 2

Proposed signaling pathways underlying the BK channel downregulation through E3 ubiquitin ligases in coronary smooth muscle cells. In diabetes, increased PKC stimulation overproduced ROS, which inhibits the PI3k/Akt pathway. Decreased Akt phosphorylation suppresses FOXO-3a and then upregulates FBXO expression. Nrf2 is downregulated in diabetic coronary smooth muscle cells. Decreased Nrf2 upregulates NF-κB and MuRF1. FBXO and MuRF1 are muscle-specific E3 ubiquitin ligases, which enhance the ubiquitination and the degradation of the BK β1-subunit. The coronary vasoconstriction in diabetes is increased due to the impaired BK channel expression and function. PKC, protein kinase C; ROS, reactive oxygen species; PI3k, phosphatidylinositide 3-kinases; FOXO-3a, the forkhead box O family transcription factor-3a; FBXO, F-box protein; Nrf2, nuclear factor E2-related factor 2; NF-κB, nuclear factor kappa B; MuRF1, muscle RING finger protein 1.