A secretagogin locus of the mammalian hypothalamus controls stress hormone release

Roman A Romanov, Alán Alpár, Ming‐Dong Zhang, Amit Zeisel, André Calas, Marc Landry, Matthew Fuszard, Sally L Shirran, Robert Schnell, Árpád Dobolyi, Márk Oláh, Lauren Spence, Jan Mulder, Henrik Martens, Miklós Palkovits, Mathias Uhlen, Harald H Sitte, Catherine H Botting, Ludwig Wagner, Sten Linnarsson, Tomas Hökfelt, Tibor Harkany
EMBO J. 2014-11-27; 34(1): 36-54
DOI: 10.15252/embj.201488977

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1. 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.

Romanov RA(1), Alpár A(2), Zhang MD(1), Zeisel A(3), Calas A(4), Landry M(4),
Fuszard M(5), Shirran SL(5), Schnell R(3), Dobolyi Á(6), Oláh M(7), Spence L(8),
Mulder J(9), Martens H(10), Palkovits M(11), Uhlen M(12), Sitte HH(13), Botting
CH(5), Wagner L(14), Linnarsson S(3), Hökfelt T(15), Harkany T(16).

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 .
(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
.

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.

© 2014 The Authors.

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

Auteurs Bordeaux Neurocampus