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  • Review Article
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The gentle art of saying NO: how nitric oxide gets things done in the hypothalamus

Nature Reviews Endocrinology volume 13, pages 521–535 (2017)Cite this article

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Key Points

  • Nitric oxide (NO) is a highly soluble and membrane-permeable neurotransmitter formed enzymatically by NO synthase (NOS) from l-arginine in equimolar amounts with l-citrulline

  • The hypothalamus is the single most important integrator of autonomic and endocrine regulation in the body, and neurons expressing neuronal NOS (nNOS) have an active role in this process

  • The activity of nNOS is tightly regulated by hormone-dependent post-transcriptional events, which include physical association with the N-methyl-D-aspartate (NMDA) receptor (the main stimulatory calcium influx pathway), and Ser1412 phosphorylation

  • In hypothalamic areas where nNOS neuron cell bodies are densely packed, NO could act as a volume transmitter to facilitate synchronous activity of specific neuroendocrine neuronal populations including gonadotropin-releasing hormone neurons

  • nNOS is hailed as a genetic risk factor for some noncommunicable diseases in which postnatal brain development (and its hormonal programming) is increasingly recognized as being a key susceptibility period.

Abstract

The chemical signalling molecule nitric oxide (NO), which freely diffuses through aqueous and lipid environments, subserves an array of functions in the mammalian central nervous system, such as the regulation of synaptic plasticity, blood flow and neurohormone secretion. In this Review, we consider the cellular and molecular mechanisms by which NO evokes short-term and long-term changes in neuronal activity. We also highlight recent studies showing that discrete populations of neurons that synthesize NO in the hypothalamus constitute integrative systems that support life by relaying metabolic and gonadal signals to the neuroendocrine brain, and thus gate the onset of puberty and adult fertility. The putative involvement and therapeutic potential of NO in the pathophysiology of brain diseases, for which hormonal imbalances during postnatal development could be risk factors, is also discussed.

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Figure 1: Splice variants of nNOS and the main activatory mechanism of nNOSα.
Figure 2: The NO–cGMP signalling pathway.
Figure 3: The hypothalamic–pituitary–gonadal axis.
Figure 4: Ovarian cycle changes proposed to regulate nNOS activity in the hypothalamic preoptic area.
Figure 5: Model of NO volume transmission in the preoptic region and its impact on GnRH neuronal function.

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Acknowledgements

The authors' work is supported by the Fondation pour la Recherche Médicale (FRM; grant number DEQ20130326524 to V.P.), The Wellcome Trust (grant number 081512/Z/06/Z to J.G.) and a doctoral fellowship from the University of Lille School of Medicine, Lille, France (to K.C.). The authors acknowledge S. Rasika for editorial assistance with the manuscript before submission and the European consortium studying GnRH biology (COST Action BM1105) coordinated by N. Pitteloud for insightful discussions.

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  1. Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, UMR-S 1172, 1 place de Verdun, Lille, F-59000, France

    Konstantina Chachlaki & Vincent Prevot

  2. University of Lille, University Hospital Federations (FHU) 1,000 days for Health, School of Medicine, 1 place de Verdun, Lille, F-59000, France

    Konstantina Chachlaki & Vincent Prevot

  3. The Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT, UK

    John Garthwaite

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K.C. researched data for the article and wrote the article. J.G. made a substantial contribution to discussions about content and reviewed and/or edited the manuscript before submission. V.P. wrote the article.

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Chachlaki, K., Garthwaite, J. & Prevot, V. The gentle art of saying NO: how nitric oxide gets things done in the hypothalamus. Nat Rev Endocrinol 13, 521–535 (2017). https://doi.org/10.1038/nrendo.2017.69

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