title: Mechanisms underlying probucol-induced hERG-channel deficiency.
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.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Yuan-Qi
authors.initials: YQ
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Cai-Chuan
authors.initials: CC
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Huai-Ze
authors.initials: HZ
authors.lastname: Geng
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lv
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China ; State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Bao-Xin
authors.initials: BX
authors.lastname: Li
mesh_terms: D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008133:Long QT Syndrome / Q000139:chemically induced*; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation / Q000187:drug effects; D011341:Probucol / Q000008:administration & dosage / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000924:Anticholesteremic Agents; D002217:Carbachol; D000072237:ERG1 Potassium Channel; D056827:Endosomal Sorting Complexes Required for Transport; D051638:Ether-A-Go-Go Potassium Channels; D017874:Immediate-Early Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D011341:Probucol; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C000606913:KCNH2 protein, human; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human
keywords: Nedd4-2; SGK1; hERG potassium channels; long QT; probucol