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, Miklõs Palkovits, Mathias Uhlen, Harald H. Sitte, Catherine H. Botting, Ludwig Wagner, Sten LinnarssonTomas Hökfelt, Tibor Harkany

Research output: Article

34 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. Synopsis Bodily responses to acute stress are orchestrated by the hierarchical release of stress hormones along the hypothalamic-pituitary-adrenal axis. Corticotropin-releasing hormone (CRH)-secreting neurons in the paraventricular nucleus of the hypothalamus are first order neurons in this axis, priming subsequent hormonal cascades upon CRH release into the portal circulation at the median eminence. Secretagogin is identified as the first neuronal Ca2+ sensor localized to parvocellular systems. The transcriptome landscape of a novel hypothalamic neuron subtype, which contains secretagogin as Ca2+ sensor, is shown. Secretagogin's Ca2+-dependent protein interactome minimally required for regulated CRH release is defined. Secretagogin is recognized to rate-limit CRH release, thus limiting hormonal responses to stress. Bodily responses to acute stress are orchestrated by the hierarchical release of stress hormones along the hypothalamic-pituitary-adrenal axis. Corticotropin-releasing hormone (CRH)-secreting neurons in the paraventricular nucleus of the hypothalamus are first order neurons in this axis, priming subsequent hormonal cascades upon CRH release into the portal circulation at the median eminence.

Original languageEnglish
Pages (from-to)36-54
Number of pages19
JournalEMBO Journal
Volume34
Issue number1
DOIs
Publication statusPublished - jan. 2 2015

    Fingerprint

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Romanov, R. A., Alpár, A., Zhang, M. D., Zeisel, A., Calas, A., Landry, M., Fuszard, M., Shirran, S. L., Schnell, R., Dobolyi, Á., Oláh, M., Spence, L., Mulder, J., Martens, H., Palkovits, M., Uhlen, M., Sitte, H. H., Botting, C. H., Wagner, L., ... Harkany, T. (2015). A secretagogin locus of the mammalian hypothalamus controls stress hormone release. EMBO Journal, 34(1), 36-54. https://doi.org/10.15252/embj.201488977