title: Gq Protein-Coupled Membrane-Initiated Estrogen Signaling Rapidly Excites Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus in Female Mice.
abstract: CRH neurons in the hypothalamic paraventricular nucleus (PVN) play a central role in regulating the hypothalamus-pituitary-adrenal (HPA) axis and are directly influenced by 17β-estradiol (E2). Although compelling evidence has suggested the existence of membrane-associated estrogen receptors (mERs) in hypothalamic and other central nervous system neurons, it remains unknown whether E2 impacts CRH neuronal excitability through this mechanism. The purpose of the current study is to examine the existence and function of mER signaling in PVN CRH neurons. Whole-cell recordings were made from CRH neurons identified by Alexa Fluor 594 labeling and post hoc immunostaining in ovariectomized female mice. E2 (100nM) rapidly suppressed the M-current (a voltage-dependent K(+) current) and potentiated glutamatergic excitatory postsynaptic currents. The putative Gq-coupled mER (Gq-mER) characterized in hypothalamic proopiomelanocortin neurons initiates a phospholipase C-protein kinase C-protein kinase A pathway; therefore, we examined the involvement of this pathway using selective inhibitors. Indeed, the ER antagonist ICI 182780 and inhibitors of Gq-phospholipase C-protein kinase C-protein kinase A blocked E2's actions, suggesting dependence on the Gq-mER. Furthermore, STX, a selective ligand for the Gq-mER, mimicked E2's actions. Finally, to examine the in vivo effect of Gq-mER activation, E2 or STX injection increased c-fos expression in CRH neurons in the PVN, suggesting CRH neuronal activation. This corresponded to an increase in plasma corticosterone. We conclude that the Gq-mER plays a critical role in the rapid regulation of CRH neuronal activity and the HPA axis. Our findings provide a potential underlying mechanism for E2's involvement in the pathophysiology of HPA-associated mood disorders.
authors.affiliation: Department of Animal Sciences (P.H., A.Y., J.D.G., N.T.B., T.A.R.), School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, and Child Health Institute of New Jersey (J.L., Z.P.P.) and Department of Neuroscience and Cell Biology (J.L., Z.P.P.), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Pu
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Animal Sciences (P.H., A.Y., J.D.G., N.T.B., T.A.R.), School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, and Child Health Institute of New Jersey (J.L., Z.P.P.) and Department of Neuroscience and Cell Biology (J.L., Z.P.P.), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Animal Sciences (P.H., A.Y., J.D.G., N.T.B., T.A.R.), School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, and Child Health Institute of New Jersey (J.L., Z.P.P.) and Department of Neuroscience and Cell Biology (J.L., Z.P.P.), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Ali
authors.initials: A
authors.lastname: Yasrebi
authors.affiliation: Department of Animal Sciences (P.H., A.Y., J.D.G., N.T.B., T.A.R.), School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, and Child Health Institute of New Jersey (J.L., Z.P.P.) and Department of Neuroscience and Cell Biology (J.L., Z.P.P.), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Juliet D
authors.initials: JD
authors.lastname: Gotthardt
authors.affiliation: Department of Animal Sciences (P.H., A.Y., J.D.G., N.T.B., T.A.R.), School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, and Child Health Institute of New Jersey (J.L., Z.P.P.) and Department of Neuroscience and Cell Biology (J.L., Z.P.P.), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Bello
authors.affiliation: Department of Animal Sciences (P.H., A.Y., J.D.G., N.T.B., T.A.R.), School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, and Child Health Institute of New Jersey (J.L., Z.P.P.) and Department of Neuroscience and Cell Biology (J.L., Z.P.P.), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Zhiping P
authors.initials: ZP
authors.lastname: Pang
authors.affiliation: Department of Animal Sciences (P.H., A.Y., J.D.G., N.T.B., T.A.R.), School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, and Child Health Institute of New Jersey (J.L., Z.P.P.) and Department of Neuroscience and Cell Biology (J.L., Z.P.P.), Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Troy A
authors.initials: TA
authors.lastname: Roepke
mesh_terms: D000178:Acrylamides; D000813:Anilides / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004958:Estradiol / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D009570:Nitriles; D010286:Paraventricular Hypothalamic Nucleus / Q000502:physiology*; D011422:Propionates; D051745:Protein Kinase C-delta / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; C553231:2-(4-hydroxyphenyl)-3-phenylpent-2-enoic acid (4-(2-dimethylaminoethoxy)phenyl)amide; D000178:Acrylamides; D000813:Anilides; D009570:Nitriles; D011422:Propionates; D004958:Estradiol; D003346:Corticotropin-Releasing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D051745:Protein Kinase C-delta; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11