title: A secretagogin locus of the mammalian hypothalamus controls stress hormone release.
abstract: A hierarchical hormonal cascade along the hypothalamic-pituitary-adrenal axis orchestrates bodily responses to stress. Although corticotropin-releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin's Ca(2+) sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin's loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness.
authors.affiliation: Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Romanov
authors.affiliation: Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden alpar.alan@med.semmelweis-univ.hu Tibor.Harkany@ki.se.
authors.forename: Alán
authors.initials: A
authors.lastname: Alpár
authors.affiliation: Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ming-Dong
authors.initials: MD
authors.lastname: Zhang
authors.affiliation: Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Amit
authors.initials: A
authors.lastname: Zeisel
authors.affiliation: Laboratory for Central Mechanisms of Pain Sensitization, Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 Université Bordeaux 2, Bordeaux, France.
authors.forename: André
authors.initials: A
authors.lastname: Calas
authors.affiliation: Laboratory for Central Mechanisms of Pain Sensitization, Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 Université Bordeaux 2, Bordeaux, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Landry
authors.affiliation: School of Chemistry, University of St. Andrews, St. Andrews, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Fuszard
authors.affiliation: School of Chemistry, University of St. Andrews, St. Andrews, UK.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Shirran
authors.affiliation: Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Schnell
authors.affiliation: Department of Anatomy, Semmelweis University, Budapest, Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Dobolyi
authors.affiliation: Department of Human Morphology and Developmental Biology, Semmelweis University, Budapest, Hungary.
authors.forename: Márk
authors.initials: M
authors.lastname: Oláh
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Spence
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Mulder
authors.affiliation: Synaptic Systems GmbH, Göttingen, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Martens
authors.affiliation: Human Brain Tissue Bank and Laboratory, Semmelweis University, Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Palkovits
authors.affiliation: Science for Life Laboratory, Albanova University Center, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlen
authors.affiliation: Center for Physiology and Pharmacology, Institute of Pharmacology Medical University of Vienna, Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.affiliation: School of Chemistry, University of St. Andrews, St. Andrews, UK.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Botting
authors.affiliation: University Clinic for Internal Medicine III General Hospital Vienna, Vienna, Austria.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wagner
authors.affiliation: Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Linnarsson
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Hökfelt
authors.affiliation: Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria alpar.alan@med.semmelweis-univ.hu Tibor.Harkany@ki.se.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000235:genetics / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D064046:Secretagogins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D059467:Transcriptome / Q000502:physiology
chemical_list: C576557:SCGN protein, mouse; D064046:Secretagogins; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: Ca2+ sensor; HPA axis; acute stress; vesicular release