title: 5-HT1A receptor-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) is modulated by regulator of G protein signaling protein 19.
abstract: The 5-HT1A receptor is a G protein coupled receptor (GPCR) that activates G proteins of the Gαi/o family. 5-HT1A receptors expressed in the raphe, hippocampus and prefrontal cortex are implicated in the control of mood and are targets for anti-depressant drugs. Regulators of G protein signaling (RGS) proteins are members of a large family that play important roles in signal transduction downstream of G protein coupled receptors (GPCRs). The main role of RGS proteins is to act as GTPase accelerating proteins (GAPs) to dampen or negatively regulate GPCR-mediated signaling. We have shown that a mouse expressing Gαi2 that is insensitive to all RGS protein GAP activity has an anti-depressant-like phenotype due to increased signaling of postsynaptic 5-HT1A receptors, thus implicating the 5-HT1A receptor-Gαi2 complex as an important target. Here we confirm that RGS proteins act as GAPs to regulate signaling to adenylate cyclase and the mitogen-activated protein kinase (MAPK) pathway downstream of the 5-HT1A receptor, using RGS-insensitive Gαi2 protein expressed in C6 cells. We go on to use short hairpin RNA (shRNA) to show that RGS19 is responsible for the GAP activity in C6 cells and also that RGS19 acts as a GAP for 5-HT1A receptor signaling in human neuroblastoma SH-SY5Y cells and primary hippocampal neurons. In addition, in both cell types the synergy between 5-HT1A receptor and the fibroblast growth factor receptor 1 in stimulating the MAPK pathway is enhanced following shRNA reduction of RGS19 expression. Thus RGS19 may be a viable new target for anti-depressant medications.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Terauchi
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Yee
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Umemori
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. Electronic address: jtraynor@umich.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D020710:RGS Proteins; D034741:RNA, Small Interfering; C097187:regulator of G-protein signalling 19; D016222:Fibroblast Growth Factor 2; D044282:Receptor, Serotonin, 5-HT1A; C098799:RGS4 protein; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051960:GTP-Binding Protein alpha Subunit, Gi2; D000262:Adenylyl Cyclases
keywords: FGF2; Hippocampal neurons; MAP kinase; Regulator of G protein signaling; SH-SY5Y cells; Serotonin 1A receptor (5-HT1A)