Impairment of human ether-à-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. Similar phenotypes but different mechanisms.
Hyperglycemia and hypoglycemia both can cause prolongation of the Q-T interval and ventricular arrhythmias. Here we studied modulation of human ether-à-go-go-related gene (HERG) K(+) channel, the major molecular component of delayed rectifier K(+) current responsible for cardiac repolarization, by glucose in HEK293 cells using whole-cell patch clamp techniques. We found that both hyperglycemia (extracellular glucose concentration [Glu](o) = 10 or 20 mm) and hypoglycemia ([Glu](o) = 2.5, 1, or 0 mm) impaired HERG function by reducing HERG current (I(HERG)) density, as compared with normoglycemia ([Glu](o) = 5 mm). Complete inhibition of glucose metabolism (glycolysis and oxidative phosphorylation) by 2-deoxy-d-glucose mimicked the effects of hypoglycemia, but inhibition of glycolysis or oxidative phosphorylation alone did not cause I(HERG) depression. Depletion of intracellular ATP mimicked the effects of hypoglycemia, and replacement of ATP by GTP or non-hydrolysable ATP failed to prevent the effects. Inhibition of oxidative phosphorylation by NaCN or application of antioxidants vitamin E or superoxide dismutase mimetic (Mn(III) tetrakis(4-benzoic acid) porphyrin chloride) abrogated and incubation with xanthine/xanthine oxidase mimicked the effects of hyperglycemia. Hyperglycemia or xanthine/xanthine oxidase markedly increased intracellular levels of reactive oxygen species, as measured by 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA) fluorescence dye, and this increase was prevented by NaCN, vitamin E, or Mn(III) tetrakis(4-benzoic acid) porphyrin chloride. We conclude that ATP, derived from either glycolysis or oxidative phosphorylation, is critical for normal HERG function; depression of I(HERG) in hypoglycemia results from underproduction of ATP and in hyperglycemia from overproduction of reactive oxygen species. Impairment of HERG function might contribute to Q-T prolongation caused by hypoglycemia and hyperglycemia.
Zhang
Yiqiang
Y
Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.
Han
Hong
H
Wang
Jingxiong
J
Wang
Huizhen
H
Yang
Baofeng
B
Wang
Zhiguo
Z
D000255:Adenosine Triphosphate / Q000502:physiology; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005947:Glucose / Q000494:pharmacology; D006019:Glycolysis; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000503:physiopathology*; D007003:Hypoglycemia / Q000150:complications / Q000503:physiopathology*; D008133:Long QT Syndrome / Q000209:etiology; D010085:Oxidative Phosphorylation; D010641:Phenotype; D010766:Phosphorylation; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D017382:Reactive Oxygen Species; D012966:Sodium Cyanide / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014810:Vitamin E / Q000494:pharmacology
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014810:Vitamin E; D000255:Adenosine Triphosphate; D005947:Glucose; D012966:Sodium Cyanide