title: Intracellular ATP binding is required to activate the slowly activating K+ channel I(Ks).
abstract: Gating of ion channels by ligands is fundamental to cellular function, and ATP serves as both an energy source and a signaling molecule that modulates ion channel and transporter functions. The slowly activating K(+) channel I(Ks) in cardiac myocytes is formed by KCNQ1 and KCNE1 subunits that conduct K(+) to repolarize the action potential. Here we show that intracellular ATP activates heterologously coexpressed KCNQ1 and KCNE1 as well as I(Ks) in cardiac myocytes by directly binding to the C terminus of KCNQ1 to allow the pore to open. The channel is most sensitive to ATP near its physiological concentration, and lowering ATP concentration in cardiac myocytes results in I(Ks) reduction and action potential prolongation. Multiple mutations that suppress I(Ks) by decreasing the ATP sensitivity of the channel are associated with the long QT (interval between the Q and T waves in electrocardiogram) syndrome that predisposes afflicted individuals to cardiac arrhythmia and sudden death. A cluster of basic and aromatic residues that may form a unique ATP binding site are identified; ATP activation of the wild-type channel and the effects of the mutations on ATP sensitivity are consistent with an allosteric mechanism. These results demonstrate the activation of an ion channel by intracellular ATP binding, and ATP-dependent gating allows I(Ks) to couple myocyte energy state to its electrophysiology in physiologic and pathologic conditions.
authors.affiliation: Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Junyuan
authors.initials: J
authors.lastname: Gao
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Lu
authors.forename: Kelli
authors.initials: K
authors.lastname: McFarland
authors.forename: Jingyi
authors.initials: J
authors.lastname: Shi
authors.forename: Kevin
authors.initials: K
authors.lastname: Bock
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.forename: Jianmin
authors.initials: J
authors.lastname: Cui
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D015153:Blotting, Western; D005470:Fluorometry; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D016296:Mutagenesis; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014982:Xenopus laevis
chemical_list: D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D000255:Adenosine Triphosphate
keywords: heart failure; ischemia