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Zhang Y, Han H, Wang J, Wang H, Yang B, Wang Z: Impairment of human ether-a-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. J Biol Chem. 2003 Mar 21;278(12):10417-26. Epub 2003 Jan 16.
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-a-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. |
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