title: Modulation of primary cilia length by melanin-concentrating hormone receptor 1.
abstract: Melanin-concentrating hormone (MCH) receptor 1 (MCHR1) is a class A G-protein-coupled receptor (GPCR). The MCH-MCHR1 system has been implicated in the regulation of feeding, emotional processing, and sleep in rodents. Recent work revealed that MCHR1 is selectively expressed in neuronal primary cilia of the central nervous system. Cilia have various chemosensory functions in many types of cell, and ciliary dysfunction is associated with ciliopathies such as polycystic kidney disease and obesity. Although dynamic modulation of neuronal cilia length is observed in obese mice, the functional interaction of neuronal ciliary GPCR and its endogenous ligand has not yet been elucidated. We report here that MCH treatment significantly reduced cilia length in hTERT-RPE1 cells (hRPE1 cells) transfected with MCHR1. Quantitative analyses indicated that MCH-induced cilia shortening progressed in a dose-dependent manner with an EC50 lower than 1nM when cells were treated for 6h. Although the assembly and disassembly of primary cilia are tightly coupled to the cell cycle, cell cycle reentry was not a determinant of MCH-induced cilia shortening. We confirmed that MCH elicited receptor internalization, Ca(2+) mobilization, ERK and Akt phosphorylation, and inhibition of cyclic AMP accumulation in MCHR1-expressing hRPE1 cells. Among these diverse pathways, we revealed that Gi/o-dependent Akt phosphorylation was an important component in the initial stage of MCH-induced cilia length shortening. Furthermore, induction of fewer cilia by Kif3A siRNA treatment significantly decreased the MCH-mediated phosphorylation of Akt, indicating the functional importance of the MCHR1-Akt pathway in primary cilia. Taken together, the present data suggest that the MCH-MCHR1 axis may modulate the sensitivity of cells to external environments by controlling the cilia length. Therefore, further characterization of MCHR1 as a ciliary GPCR will provide a potential molecular mechanism to link cilia length control with obesity.
authors.affiliation: Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Hamamoto
authors.affiliation: Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamato
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Katoh
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Anatomy and Cell Biology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Anatomy and Cell Biology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan. Electronic address: yumist@hiroshima-u.ac.jp.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000648:ultrastructure; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C491208:MCHR1 protein, rat; D017481:Receptors, Somatostatin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Akt pathway; G-protein; G-protein-coupled receptor (GPCR); Melanin-concentrating hormone (MCH); Melanin-concentrating hormone receptor 1 (MCHR1); Primary cilia