title: Ginsenoside Re, a main phytosterol of Panax ginseng, activates cardiac potassium channels via a nongenomic pathway of sex hormones.
abstract: Ginseng root is one of the most popular herbs throughout the world and is believed to be a panacea and to promote longevity. It has been used as a medicine to protect against cardiac ischemia, a major cause of death in the West. We have previously demonstrated that ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca(2+) accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca(2+) channel inhibition and K(+) channel activation in cardiac myocytes. In this study, we provide compelling evidence that ginsenoside Re activates endothelial NO synthase (eNOS) to release NO, resulting in activation of the slowly activating delayed rectifier K(+) current. The eNOS activation occurs via a nongenomic pathway of each of androgen receptor, estrogen receptor-alpha, and progesterone receptor, in which c-Src, phosphoinositide 3-kinase, Akt, and eNOS are sequentially activated. However, ginsenoside Re does not stimulate proliferation of androgen-responsive LNCaP cells and estrogen-responsive MCF-7 cells, implying that ginsenoside Re does not activate a genomic pathway of sex hormone receptors. Fluorescence resonance energy transfer experiments with a probe, SCCoR (single cell coactivator recruitment), indicate that the lack of genomic action is attributable to failure of coactivator recruitment. Thus, ginsenoside Re acts as a specific agonist for the nongenomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K(+) channel activation and protection against ischemia-reperfusion injury.
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. t_furukawa.bip@mri.tmd.ac.jp
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
authors.forename: Chang-Xi
authors.initials: CX
authors.lastname: Bai
authors.forename: Asami
authors.initials: A
authors.lastname: Kaihara
authors.forename: Eri
authors.initials: E
authors.lastname: Ozaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawano
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakaya
authors.forename: Muhammad
authors.initials: M
authors.lastname: Awais
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Sato
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Umezawa
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000187:drug effects; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D036145:Ginsenosides / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D005894:Panax / Q000737:chemistry*; D010766:Phosphorylation; D015221:Potassium Channels / Q000819:agonists*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects; D011980:Receptors, Progesterone / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D036145:Ginsenosides; D015221:Potassium Channels; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D009569:Nitric Oxide; C049864:ginsenoside Re; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt