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EMBO J. 2015 Jan 2;34(1):36-54. doi: 10.15252/embj.201488977. Epub 2014 Nov 27.

A secretagogin locus of the mammalian hypothalamus controls stress hormone release.

Author information

1
Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
2
Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden alpar.alan@med.semmelweis-univ.hu Tibor.Harkany@ki.se.
3
Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden.
4
Laboratory for Central Mechanisms of Pain Sensitization, Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 Université Bordeaux 2, Bordeaux, France.
5
School of Chemistry, University of St. Andrews, St. Andrews, UK.
6
Department of Anatomy, Semmelweis University, Budapest, Hungary.
7
Department of Human Morphology and Developmental Biology, Semmelweis University, Budapest, Hungary.
8
Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
9
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
10
Synaptic Systems GmbH, Göttingen, Germany.
11
Human Brain Tissue Bank and Laboratory, Semmelweis University, Budapest, Hungary.
12
Science for Life Laboratory, Albanova University Center, Royal Institute of Technology, Stockholm, Sweden.
13
Center for Physiology and Pharmacology, Institute of Pharmacology Medical University of Vienna, Vienna, Austria.
14
University Clinic for Internal Medicine III General Hospital Vienna, Vienna, Austria.
15
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
16
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.

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.

KEYWORDS:

Ca2+ sensor; HPA axis; acute stress; vesicular release

PMID:
25430741
PMCID:
PMC4291479
DOI:
10.15252/embj.201488977
[Indexed for MEDLINE]
Free PMC Article

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