Referenced in: none

Automatically associated channels: Kv11.1

Title: Mechanisms underlying probucol-induced hERG-channel deficiency.

Authors: Yuan-Qi Shi, Cai-Chuan Yan, Xiao Zhang, Meng Yan, Li-Rong Liu, Huai-Ze Geng, Lin Lv, Bao-Xin Li

Journal, date & volume: Drug Des Devel Ther, 2015 , 9, 3695-704

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26229434

Abstract
The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (I Kr), which is important for cardiac repolarization. Reduction of I hERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes) or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on I hERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.