title: High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition.
abstract: OBJECTIVE
  Abnormal QT prolongation is the most prominent cardiac electrical disturbance in patients with diabetes mellitus (DM). It is well known that the human ether-ago-go-related gene (hERG) controls the rapid delayed rectifier K+ current (IKr) in cardiac cells. The expression of the hERG channel is severely down-regulated in diabetic hearts, and this down-regulation is a critical contributor to the slowing of repolarization and QT prolongation. However, the intracellular mechanisms underlying the diabetes-induced hERG deficiency remain unknown.
  
  
  METHODS
  The expression of the hERG channel was assessed via western blot analysis, and the hERG current was detected with a patch-clamp technique.
  
  
  RESULTS
  The results of our study revealed that the expression of the hERG protein and the hERG current were substantially decreased in high-glucose-treated hERG-HEK cells. Moreover, we demonstrated that the high-glucose-mediated damage to the hERG channel depended on the down-regulation of protein levels but not the alteration of channel kinetics. These discoveries indicated that high glucose likely disrupted hERG channel trafficking. From the western blot and immunoprecipitation analyses, we found that high glucose induced trafficking inhibition through an effect on the expression of Hsp90 and its interaction with hERG. Furthermore, the high-glucose-induced inhibition of hERG channel trafficking could activate the unfolded protein response (UPR) by up-regulating the expression levels of activating transcription factor-6 (ATF-6) and the ER chaperone protein calnexin. In addition, we demonstrated that 100 nM insulin up-regulated the expression of the hERG channel and rescued the hERG channel repression caused by high glucose.
  
  
  CONCLUSIONS
  The results of our study provide the first evidence of a high-glucose-induced hERG channel deficiency resulting from the inhibition of channel trafficking. Furthermore, insulin promotes the expression of the hERG channel and ameliorates the high-glucose-induced inhibition of the hERG channel.
authors: Department of Pharmacology, Harbin Medical University, Harbin, China.
authors: Yuan-Qi
authors: YQ
authors: Shi
authors: Meng
authors: M
authors: Yan
authors: Li-Rong
authors: LR
authors: Liu
authors: Xiao
authors: X
authors: Zhang
authors: Xue
authors: X
authors: Wang
authors: Huai-Ze
authors: HZ
authors: Geng
authors: Xin
authors: X
authors: Zhao
authors: Bao-Xin
authors: BX
authors: Li
mesh_terms: D000200:Action Potentials / Q000502:physiology; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006329:Heart Conduction System / Q000002:abnormalities / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D021381:Protein Transport / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D018841:HSP90 Heat-Shock Proteins; D007328:Insulin; D005947:Glucose