title: Hydrogen Sulfide Targets the Cys320/Cys529 Motif in Kv4.2 to Inhibit the Ito Potassium Channels in Cardiomyocytes and Regularizes Fatal Arrhythmia in Myocardial Infarction.
abstract: OBJECTIVE
  The mechanisms underlying numerous biological roles of hydrogen sulfide (H2S) remain largely unknown. We have previously reported an inhibitory role of H2S in the L-type calcium channels in cardiomyocytes. This prompts us to examine the mechanisms underlying the potential regulation of H2S on the ion channels.
  
  
  RESULTS
  H2S showed a novel inhibitory effect on Ito potassium channels, and this effect was blocked by mutation at the Cys320 and/or Cys529 residues of the Kv4.2 subunit. H2S broke the disulfide bridge between a pair of oxidized cysteine residues; however, it did not modify single cysteine residues. H2S extended action potential duration in epicardial myocytes and regularized fatal arrhythmia in a rat model of myocardial infarction. H2S treatment significantly increased survival by ∼1.4-fold in the critical 2-h time window after myocardial infarction with a protection against ventricular premature beats and fatal arrhythmia. However, H2S did not change the function of other ion channels, including IK1 and INa.
  
  
  CONCLUSIONS
  H2S targets the Cys320/Cys529 motif in Kv4.2 to regulate the Ito potassium channels. H2S also shows a potent regularizing effect against fatal arrhythmia in a rat model of myocardial infarction. The study provides the first piece of evidence for the role of H2S in regulating Ito potassium channels and also the specific motif in an ion channel labile for H2S regulation.
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .|2 Department of Physiology, Bengbu Medical College , Bengbu, China .
authors.forename: Shan-Feng
authors.initials: SF
authors.lastname: Ma
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Ying-Jiong
authors.initials: YJ
authors.lastname: Ding
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Shi-Xin
authors.initials: SX
authors.lastname: Pu
authors.affiliation: 3 Institutes of Brain Science, Institute of Neurobiology and State Key Laboratory of Medical Neurobiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Hang-Jing
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: 3 Institutes of Brain Science, Institute of Neurobiology and State Key Laboratory of Medical Neurobiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Zhong-Feng
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Tao
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Wang
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules and Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai, China .
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Zhu
mesh_terms: D020816:Amino Acid Motifs / Q000187:drug effects*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004220:Disulfides; D051672:Shal Potassium Channels; D003545:Cysteine; D006862:Hydrogen Sulfide