Glucocorticoids desensitize hypothalamic CRH neurons to norepinephrine and somatic stress activation via rapid nitrosylation-dependent regulation of α1 adrenoreceptor trafficking.

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 α1 adrenoreceptor (ARα1) trafficking is regulated by convergent glucocorticoid and nitric oxide synthase signaling mechanisms. Live-cell imaging of ARα1b-eGFP-expressing hypothalamic cells revealed rapid corticosterone-stimulated redistribution of internalized ARα1 from rapid recycling endosomes to late endosomes and lysosomes via a nitrosylation-regulated mechanism. Proximity assay demonstrated interaction of glucocorticoid receptors with ARα1b and β-arrestin, and showed corticosterone blockade of norepinephrine-stimulated ARα1b/β-arrestin interaction, which may prevent ARα1b 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.