title: A charged residue in S4 regulates coupling among the activation gate, voltage, and Ca2+ sensors in BK channels.
abstract: Coupling between the activation gate and sensors of physiological stimuli during ion channel activation is an important, but not well-understood, molecular process. One difficulty in studying sensor-gate coupling is to distinguish whether a structural perturbation alters the function of the sensor, the gate, or their coupling. BK channels are activated by membrane voltage and intracellular Ca(2+) via allosteric mechanisms with coupling among the activation gate and sensors quantitatively defined, providing an excellent model system for studying sensor-gate coupling. By studying BK channels expressed in Xenopus oocytes, here we show that mutation E219R in S4 alters channel function by two independent mechanisms: one is to change voltage sensor activation, shifting voltage dependence, and increase valence of gating charge movements; the other is to regulate coupling among the activation gate, voltage sensor, and Ca(2+) binding via electrostatic interactions with E321/E324 located in the cytosolic side of S6 in a neighboring subunit, resulting in a shift of the voltage dependence of channel opening and increased Ca(2+) sensitivity. These results suggest a structural arrangement of the inner pore of BK channels differing from that in other voltage gated channels.
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of California at San Francisco, San Francisco, California 94143, and.
authors.forename: Huanghe
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130.
authors.forename: Junqiu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130.
authors.forename: Kelli
authors.initials: K
authors.lastname: McFarland
authors.affiliation: Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China (Tongji University), Shanghai 200120, China.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou 215123, China, jcui@wustl.edu.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Cui
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism*; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000502:physiology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D009865:Oocytes / Q000502:physiology*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000596:Amino Acids; D051036:Large-Conductance Calcium-Activated Potassium Channels; D002118:Calcium
keywords: BK channels; coupling; intersubunit interaction; pore-gate; voltage sensor