title: The atypical antipsychotic, olanzapine, potentiates ghrelin-induced receptor signaling: An in vitro study with cells expressing cloned human growth hormone secretagogue receptor.
abstract: The growth hormone secretagogue receptor (GHS-R) belongs to Gαq-coupled G protein-coupled receptor (GPCR) that mediates growth hormone release, food intake, appetite, glucose metabolism and body composition. Ghrelin has been identified as an endogenous ligand for GHS-R, and it is the only orexigenic peptide found in the peripheral organs. Olanzapine, an atypical antipsychotic agent that binds to and inhibits the activation of GPCR for several neurotransmitters, has metabolic side effects such as excessive appetite and weight gain. Recently, studies have revealed that the orexigenic mechanism of olanzapine is mediated via GHS-R signaling, although the precise mechanisms have not been clarified. In this study, we investigated the effect of olanzapine on ghrelin-mediated GHS-R signaling by using an electrical impedance-based receptor biosensor assay system (CellKey™). Olanzapine at concentrations of 10(-7) and 10(-6)mol/L enhanced ghrelin-induced (10(-10)-10(-8)mol/L) GHS-R activation. A Ca(2+) imaging assay revealed that olanzapine (10(-7) and 10(-6)mol/L) enhanced ghrelin (10(-7) M)-induced GHS-R activity. In contrast, haloperidol (an antipsychotic agent) failed to enhance this ghrelin-mediated GHS-R activation, as demonstrated by both the CellKey™ and Ca(2+) imaging assays. Together, these results suggest that olanzapine, but not haloperidol, promotes appetite by enhancing ghrelin-mediated GHS-R signaling.
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Palliative Medicine, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan; Division of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, 2-1-1 Hongou, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: ktagami@ncc.go.jp.
authors.forename: Keita
authors.initials: K
authors.lastname: Tagami
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Division of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-0022, Japan. Electronic address: yohei090109@outlook.jp.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kashiwase
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Division of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-0022, Japan. Electronic address: ayoko65@gmail.com.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Yokoyama
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Division of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-0022, Japan. Electronic address: 3B14679@ed.tus.ac.jp.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: kmiyano@ncc.go.jp.
authors.forename: Kanako
authors.initials: K
authors.lastname: Miyano
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: masamsuz@ncc.go.jp.
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: sshirais@ncc.go.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shiraishi
authors.affiliation: Department of Palliative Medicine, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shiguya-ku, Tokyo 150-8935, Japan. Electronic address: teamkanwa@gmail.com.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Matoba
authors.affiliation: Division of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, 2-1-1 Hongou, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: yohe@ncc.go.jp.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Division of Supportive Care Research, National Cancer Center Exploratory Oncology Research and Clinical Trial Center Research, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Innovation Center for Supportive, Palliative and Psychosocial Care, National Cancer Center, 5-1-1 Tsukiji, Tokyo 104-0045, Japan. Electronic address: yuezono@ncc.go.jp.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002460:Cell Line; D054439:Ghrelin / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000077152:Olanzapine; D054440:Receptors, Ghrelin / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D054439:Ghrelin; D054440:Receptors, Ghrelin; D001569:Benzodiazepines; D006220:Haloperidol; D000077152:Olanzapine
keywords: Anorexia; Appetite; Ca(2+) imaging assay; CellKey™ system; Ghrelin; Growth hormone secretagogue receptor; Haloperidol; Olanzapine