title: Ginseng gintonin activates the human cardiac delayed rectifier K+ channel: involvement of Ca2+/calmodulin binding sites.
abstract: Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits [Ca(2+)]i transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier K(+) (I(Ks)) channel is a cardiac K(+) channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating I(Ks) channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human I(Ks) channel activity by expressing human I(Ks) channels in Xenopus oocytes. We found that gintonin enhances IKs channel currents in concentration- and voltage-dependent manners. The EC50 for the I(Ks) channel was 0.05 ± 0.01 μg/ml. Gintonin-mediated activation of the I(Ks) channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an IP3 receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the I(Ks) channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 [Ca(2+)]i/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on I(Ks) channel. However, gintonin had no effect on hERG K(+) channel activity. These results show that gintonin-mediated enhancement of I(Ks) channel currents is achieved through binding of the [Ca(2+)]i/CaM complex to the C terminus of KCNQ1 subunit.
authors.affiliation: Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea.
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea.
authors.forename: Byung-Hwan
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea.
authors.forename: Hyeon-Joong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea.
authors.forename: Seok-Won
authors.initials: SW
authors.lastname: Jung
authors.affiliation: Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea.
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Korea.
authors.forename: Ho-Chul
authors.initials: HC
authors.lastname: Shin
authors.affiliation: Department of Physical Therapy, College of Health Science, Cheongju University, Cheongju 360-764, Korea.
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Life Science Division, Korea Institute of Science and Technology, Seoul 136-791, Korea.
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.affiliation: Department of Pharmaceutical Engineering College of Health Sciences Sangji University, Wonju 220-702, Korea.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Biomedical Science, Daegu University, Gyeonsan 712-714, Korea.
authors.forename: Tal Soo
authors.initials: TS
authors.lastname: Ha
authors.affiliation: Department of Physiology and Samsung Biomedical Research Institute, School of Medicine, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Physiology and Samsung Biomedical Research Institute, School of Medicine, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea.
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002147:Calmodulin / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D005894:Panax / Q000737:chemistry*; D010940:Plant Proteins / Q000737:chemistry / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D002147:Calmodulin; D051668:Delayed Rectifier Potassium Channels; D007555:Isoxazoles; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C000598969:MLP151 protein, Panax ginseng; D010940:Plant Proteins; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D002118:Calcium
keywords: IKs channel; LPA receptor; ginseng; gintonin; heart