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 Alexander Fuszard, Sally Lorna Shirran, Robert Schnell, Árpád Dobolyi, Márk Oláh, Lauren Spence, Jan Mulder, Henrik Martens, Miklós Palkovits, Mathias Uhlen, Harald H. Sitte, Catherine Helen Botting, Ludwig Wagner, Sten LinnarssonTomas Hökfelt, Tibor Harkany

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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 Ca2+ 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.

Original languageEnglish
Pages (from-to)36-54
JournalEMBO Journal
Volume34
Issue number1
Early online date27 Nov 2014
DOIs
Publication statusPublished - 2 Jan 2015

Keywords

  • Acute stress
  • Ca2+ sensor
  • HPA axis
  • Vesicular release

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