New Tricks for Nrf2: Therapeutic Targeting to Restore BK-β1 Expression?

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Abstract

The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) is ubiquitously expressed and a master regulator of antioxidant, phase II, and proteostatic genes induced by oxidative or electrophilic stress (1,2). Basally, Nrf2 is continually synthesized and associates with adaptor protein Kelch-like ECH-associated protein 1 (Keap1), resulting in its ubiquitination and rapid degradation via the 26S proteasome (3–5). Following oxidative challenge, modification of essential cysteine residues on Keap1 prevent Nrf2 degradation, allowing de novo Nrf2 to translocate to the nucleus and initiate transcription of target genes containing an antioxidant or electrophilic response element in their promoter region. In cells, failure to activate Nrf2 defenses increases their susceptibility to oxidative damage and dysfunction, contributing to the pathogenesis of various cardiometabolic disease states including hypertension, cardiomyopathy, gestational diabetes mellitus, and type 2 diabetes (6–8).

In this issue of Diabetes, Lu et al. (9) demonstrate a novel role for Nrf2 in the regulation of the large conductance Ca2+-activated K+ (BK) channel β1 subunit (BK-β1). As with other recently identified Nrf2-regulated solute transporters, this channel has no intrinsic antioxidant activity but is nevertheless important in homeostatic control of cell function. BK channels are expressed on vascular endothelial cells and smooth muscle cells (SMCs) and consist of a tetramer of α-subunits, containing a channel pore domain, voltage sensor, and Ca2+-sensing region. These α-subunits are each associated with a tissue-specific modulatory β-subunit (isoforms β1–4), altering channel activity (10). The β1-subunit is abundantly expressed in vascular SMCs and enhances the BK channels sensitivity to Ca2+ (11). Activation of BK channels leads to K+ efflux, resulting in membrane hyperpolarization and inhibition of Ca2+ influx through large conductance L-type Ca2+ channels, allowing BK channels to sense and modulate intracellular Ca2+ levels
Original languageEnglish
Pages (from-to)2538-2540
JournalDiabetes
Volume66
Early online date20 Sept 2017
DOIs
Publication statusPublished - Oct 2017

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