Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Yang, Silei; Roselli, Francesco; Patchev, Alexandre V.; Yu, Sheng-Bo; Almeida, Osborne F. X.

doi:10.1074/jbc.m113.470146

Cited by 36 publications

(35 citation statements)

References 65 publications

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“…Consistent with reports in other systems (41), glucocorticoids alone induced Src phosphorylation in AtT-20 cells. Although corticosterone and CRH which have converse effects of ACTH secretion had similar effects of Src phosphorylation, the facts that corticosterone prevented the early effect of CRH on Src phosphorylation, and that Src inhibitors inhibited CRH-stimulated ACTH secretion, suggest that inhibition of Src phosphorylation contributes to the rapid inhibitory effect of glucocorticoids on CRHstimulated ACTH secretion.…”

Section: Discussionsupporting

confidence: 91%

“…While the reversibility of electrophysiological effects of glucocorticoids by intracellular application of the guanyl nucleotide binding protein (G-protein) inhibitor, GDP-␤-S (40), or pertussis toxin (31,41) has suggested a G-protein coupled membrane receptor, other in vitro (30) and in vivo (42) studies have showed rapid glucocorticoid-induced inhibition of ACTH secretion reversible by a GR antagonist, concluding that the effect is mediated by the classical GR. The present experiments show complex actions of RU486, clearly blocking the early inhibitory effect of corticosterone but having a late inhibitory effect on CRH-stimulated ACTH secretion on its own.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, in cultured hippocampal neurons glucocorticoids induce rapid cytoskeletal rearrangements leading to increased surface NMDA receptor expression and inhibition of NMDA receptor endocytosis. As for other nongenomic actions (14,53,54), the latter involves activation of several protein kinases (41), including the nonreceptor tyrosine kinase, Src. Also, Src inhibitors prevent the rapid inhibition of phospholipase A 2 activity and arachidonic acid release by dexamethasone in the human adenocarcinoma cell line, A549, suggesting that the effect depends on GR-mediated activation of Src (57).…”

Section: Discussionmentioning

confidence: 99%

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Rapid Glucocorticoid Feedback Inhibition of ACTH Secretion Involves Ligand-Dependent Membrane Association of Glucocorticoid Receptors

et al. 2015

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The hypothesis that rapid glucocorticoid inhibition of pituitary ACTH secretion mediates a feedforward/feedback mechanism responsible for the hourly glucocorticoid pulsatility was tested in cultured pituitary cells. Perifusion with 30 pM CRH caused sustained the elevation of ACTH secretion. Superimposed corticosterone pulses inhibited CRH-stimulated ACTH release, depending on prior glucocorticoid clearance. When CRH perifusion started after 2 hours of glucocorticoid-free medium, corticosterone levels in the stress range (1 μM) caused a delayed (25 min) and prolonged inhibition of CRH-stimulated ACTH secretion, up to 60 minutes after corticosterone withdrawal. In contrast, after 6 hours of glucocorticoid-free medium, basal corticosterone levels inhibited CRH-stimulated ACTH within 5 minutes, after rapid recovery 5 minutes after corticosterone withdrawal. The latter effect was insensitive to actinomycin D but was prevented by the glucocorticoid receptor antagonist, RU486, suggesting nongenomic effects of the classical glucocorticoid receptor. In hypothalamic-derived 4B cells, 10 nM corticosterone increased immunoreactive glucocorticoid receptor content in membrane fractions, with association and clearance rates paralleling the effects on ACTH secretion from corticotrophs. Corticosterone did not affect CRH-stimulated calcium influx, but in AtT-20 cells, it had biphasic effects on CRH-stimulated Src phosphorylation, with early inhibition and late stimulation, suggesting a role for Src phosphorylation on the rapid glucocorticoid feedback. The data suggest that the nongenomic/membrane effects of classical GR mediate rapid and reversible glucocorticoid feedback inhibition at the pituitary corticotrophs downstream of calcium influx. The sensitivity and kinetics of these effects is consistent with the hypothesis that pituitary glucocorticoid feedback is part of the mechanism for adrenocortical ultradian pulse generation.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Rapid Glucocorticoid Feedback Inhibition of ACTH Secretion Involves Ligand-Dependent Membrane Association of Glucocorticoid Receptors

et al. 2015

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“…PYK2 is a component of the NMDAR complex (35) and is activated by NMDAR stimulation (36). In addition, a rapid response of hippocampal neurons to glucocorticoids includes activation of Pyk2 via a putative G-protein-coupled receptor (19). We show here that the subcellular distribution of activated Pyk2 (phospho-Y402 Pyk2) in hippocampal pyramidal neurons is altered in chronically stressed mice.…”

Section: Discussionmentioning

confidence: 79%

“…Hippocampal neurons respond rapidly to glucocorticoids via a G-protein-coupled membrane receptor, and downstream effectors include activation of Pyk2 (19). Activation and nuclear translocation of Pyk2 also has been observed in cultured cells treated with pervanadate [protein tyrosine phosphatase inhibitor (20,21)] and in hippocampal slices treated with depolarizing concentrations of K + (22).…”

Section: Decreased Nup62 Content In Hippocampal Neurons Exposed To Chmentioning

confidence: 99%

Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress

Kinoshita¹,

Hunter

Gray

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Genetic evidence suggests cell-type-specific functions for certain nucleoporins, and gene expression profiling has revealed that nucleoporin p62 (NUP62) transcripts are decreased in the prefrontal cortex of major depressives. Chronic stress, which can precipitate depression, induces changes in the architecture and plasticity of apical dendrites that are particularly evident in the CA3 region of the hippocampus. Genetically targeted translating ribosome affinity purification revealed a selective reduction in translated Nup62 transcripts in CA3 of chronically stressed mice, and the Nup62 protein content of nuclei extracted from whole hippocampus was found to be decreased in chronically stressed rats. In cultured cells, phosphorylation of a FAK/proline-rich tyrosine kinase 2 (PYK2) consensus site in the alpha-helical domain of NUP62 (human Y422) is shown to be associated with shedding of NUP62 from the nuclear pore complex (NPC) and/or retention of NUP62 in the cytoplasm. Increased levels of phospho-Y425 Nup62 were observed in cytoplasmic fractions of hippocampi from chronically stressed rats, and immunofluorescence microscopy revealed redistribution of activated Pyk2 to the perinuclear region of stressed pyramidal neurons. Depletion of Nup62 from cultured embryonic day 18 rat hippocampal and cortical neurons resulted in simplification and retraction of dendritic arbors, without disruption of axon initial segment integrity. Thus, at least two types of mechanisms-one affecting expression and the other association with the NPC-could contribute to loss of NUP62 from CA3 pyramidal neurons during chronic stress. Their combined actions may account for the enhanced responsiveness of CA3 apical dendrites to chronic stress and may either be pathogenic or serve to protect CA3 neurons from permanent damage.nucleoporin p62 | proline-rich tyrosine kinase 2 | chronic stress | dendrite retraction | hippocampus S ubstructures of the nuclear pore complex (NPC) are visible by electron microscopy and include an inner scaffold that interfaces the nuclear envelope, a central channel, and two asymmetric rings that project into either the cytoplasm or the nucleus (1). Selective nucleocytoplasmic transport through the NPC is mediated by phenylalanine-glycine (FG)-repeat-containing nucleoporins in the central channel and asymmetric ring structures. Some FG-repeat nucleoporins, including the central channel nucleoporin p62 (NUP62), function in transcription and chromatin organization independently of their roles in transport (2-4). Tissue-specific genetic diseases arising from mutations in nucleoporins have suggested that the NPC and/or its components can mediate celltype-specific functions (5, 6). For example, the Q391P mutation in NUP62 causes autosomal recessive infantile bilateral striatal necrosis (IBSN), a fatal degeneration of the corpus striatum that occurs during early childhood (7). Although Nup62 null mice are embryonic day 7 lethal (8), human Q391P homozygotes develop past term, suggesting that the mutation affects a specialized...

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The Multifaceted Mineralocorticoid Receptor

Gómez-Sánchez

2014

Comprehensive Physiology

261

224

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The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect.

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Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Cited by 36 publications

References 65 publications

Rapid Glucocorticoid Feedback Inhibition of ACTH Secretion Involves Ligand-Dependent Membrane Association of Glucocorticoid Receptors

Rapid Glucocorticoid Feedback Inhibition of ACTH Secretion Involves Ligand-Dependent Membrane Association of Glucocorticoid Receptors

Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress

The Multifaceted Mineralocorticoid Receptor

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