Tagami Keita, Kashiwase Yohei, Yokoyama Akinobu, Nishimura Hitomi, Miyano Kanako, Suzuki Masami, Shiraishi Seiji, Matoba Motohiro, Ohe Yuichiro, Uezono Yasuhito
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.
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.
Neuropeptides. 2016 Aug;58:93-101. doi: 10.1016/j.npep.2015.12.010. Epub 2015 Dec 22.
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.
生长激素促分泌素受体（GHS-R）属于与Gαq偶联的G蛋白偶联受体（GPCR），介导生长激素释放、食物摄取、食欲、葡萄糖代谢和身体组成。胃饥饿素已被确定为GHS-R的内源性配体，并且是在外周器官中发现的唯一促食欲肽。奥氮平是一种非典型抗精神病药物，可结合并抑制多种神经递质的GPCR激活，具有诸如食欲亢进和体重增加等代谢副作用。最近，研究表明奥氮平的促食欲机制是通过GHS-R信号传导介导的，尽管确切机制尚未阐明。在本研究中，我们使用基于电阻抗的受体生物传感器检测系统（CellKey™）研究了奥氮平对胃饥饿素介导的GHS-R信号传导的影响。浓度为10^(-7)和10^(-6)mol/L的奥氮平增强了胃饥饿素诱导的（10^(-10)-10^(-8)mol/L）GHS-R激活。Ca(2+)成像分析表明，奥氮平（10^(-7)和10^(-6)mol/L）增强了胃饥饿素（10^(-7) M）诱导的GHS-R活性。相比之下，如CellKey™和Ca(2+)成像分析所示，氟哌啶醇（一种抗精神病药物）未能增强这种胃饥饿素介导的GHS-R激活。总之，这些结果表明，奥氮平而非氟哌啶醇通过增强胃饥饿素介导的GHS-R信号传导来促进食欲。
