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bioRxiv · 10.1101/2024.07.29.605704

Glucocorticoids desensitize CRH neurons to norepinephrine via rapid nitrosylation-dependent regulation of α1 adrenoreceptor trafficking

Weiss, G. L.·Harrison, L. M.·Jiang, Z.·Nielsen, A. M.·Feygin, M. S.·Nguyen, S.·Tirrell, P. S.·Tasker, J. G.
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Abstract

Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive for somatic stress activation of the hypothalamic-pituitary-adrenal (HPA) axis. We showed that glucocorticoids rapidly desensitize CRH neurons to norepinephrine and suppress inflammation-induced HPA activation via a glucocorticoid receptor- and endocytosis-dependent mechanism. Here, we show that 1 adrenoreceptor (AR1) trafficking is regulated by convergent glucocorticoid and nitric oxide synthase signaling mechanisms. Live-cell imaging of AR1b-eGFP-expressing hypothalamic cells revealed rapid corticosterone-stimulated redistribution of internalized AR1 from rapid recycling endosomes to late endosomes and lysosomes via a nitrosylation-regulated mechanism. Proximity assay demonstrated interaction of glucocorticoid receptors with AR1b and {beta}-arrestin, and showed corticosterone blockade of norepinephrine-stimulated AR1b/{beta}-arrestin interaction, which may prevent AR1b from entering the rapid recycling endosomal pathway. These findings demonstrate a rapid glucocorticoid regulation of G protein-coupled receptor trafficking and provide a molecular mechanism for rapid glucocorticoid desensitization of noradrenergic signaling in CRH neurons.

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Weiss, G. L., Harrison, L. M., Jiang, Z., Nielsen, A. M., Feygin, M. S., Nguyen, S., Tirrell, P. S., Tasker, J. G.. 2024-07-30. Glucocorticoids desensitize CRH neurons to norepinephrine via rapid nitrosylation-dependent regulation of α1 adrenoreceptor trafficking. https://doi.org/10.1101/2024.07.29.605704

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