Regulation of Corticotropin-Releasing Factor (CRF) Receptors in the Rat Pituitary Gland: Effects of Adrenalectomy on CRF Receptors and Corticotroph Responses

Wynn, Peter; Harwood, James P.; Catt, Kevin J.; Aguilera, Greti

doi:10.1210/endo-116-4-1653

Cited by 160 publications

(87 citation statements)

References 45 publications

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“…The binding capacity of the rat ovary homogenates (Bm. = 61.17 fmol/mg protein) was in the same order of magnitude as that of rat brain cortex homogenates (Bmax = 62.19 fmol/mg protein) (32,6), one-tenth of that shown in pituitary gland (41,42), and 6 times and 20 times higher than that shown in mouse spleen (Bm. = 8.74 fmol/mg protein) (32) and in rat Leydig cells (Bm.…”

Section: Discussionmentioning

confidence: 62%

Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary.

Mastorakos¹,

Webster²,

Friedman³

et al. 1993

J. Clin. Invest.

107

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Corticotropin-releasing hormone (CRH), the principal neuropeptide regulator of pituitary AC17H secretion, is also produced at peripheral inflammatory sites, where it acts as a proinflammatory cytokine, and by the Leydig cell of the testis, where it exerts autocrine inhibition of testosterone biosynthesis. Because key ovarian functions, such as ovulation and luteolysis, represent aseptic inflammatory responses, and because the theca cell is the functional equivalent of the Leydig cell, we explored the CRH presence in the ovary, first, by specific CRH immunohistochemistry of adult cycling female Sprague-Dawley rat ovaries. We detected cytoplasmic immunoreactive CRH (IrCRH) in theca and stromal cells and in cells within the corpora lutea, at all phases of the estrous cycle. Using a specific radioimmunoassay, we measured IrCRH in extracts of rat ovaries (0.0424.126 pmol/g wet tissue). The mobility of the ovarian IrCRH molecule was similar to that of rat/human CRH by reverse phase HPLC. To investigate the CRH action in the ovary, we identified, characterized, and localized CRH receptors in the rat ovary. Binding was linear with increasing tissue concentration, saturable, and of high affinity. Scatchard analysis of '251-Tyr-ovine CRH competitive displacement curves indicated a high affinity binding site with a Kd of 6 nM and a B. value of 61 fM/mg protein. Autoradio-graphic studies revealed CRH receptors primarily in ovarian theca and stroma. We conclude that IrCRH and CRH receptors are present in rat ovaries, suggesting that this neuropeptide may play a regulatory role in this gonad, perhaps through its proinflammatory properties and/or by participating in the auto/paracrine regulation of steroid biosynthesis. Functional studies are necessary to define the role(s) of CRH in the ovary. (J. Clin. Invest. 1993. 92:961-968.)

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Section: Discussionmentioning

confidence: 62%

Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary.

Mastorakos¹,

Webster²,

Friedman³

et al. 1993

J. Clin. Invest.

107

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Section: Discussionmentioning

confidence: 99%

“…This occurs by decreasing the rate of POMC gene transcription (15,17,18). The level of CRF receptors is also decreased by glucocorticoids, but the mechanisms that mediate the down-regulation of these receptors have not been identified (5,12,13,19).Identification of the CRF receptor expressed in the pituitary makes it feasible to study the mechanisms that mediate glucocorticoid regulation of this receptor at the molecular level. The CRF receptor expressed in corticotrophic cells, referred to as CRF-R1, is positively coupled via a stimulatory G protein to the cAMP second messenger system (20).…”

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confidence: 99%

Glucocorticoid Regulation of Corticotropin-Releasing Factor₁Receptor Expression in Pituitary-Derived AtT-20 Cells

Iredale

Duman

1997

Mol Pharmacol

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SUMMARYCorticotropin-releasing factor (CRF) receptors represent one of the primary sites for negative feedback of the pituitary by adrenocortical glucocorticoid hormones; however, the molecular mechanisms involved have yet to be elucidated. The present study examines the mechanisms by which glucocorticoids regulate CRF-R1 expression in the pituitary cell line, AtT-20. Treatment of these cells with dexamethasone resulted in a concentration-and time-dependent inhibition of CRF-R1 mRNA that was significant by 1 hr and maximal after 4 hr. Levels of CRF-R1 mRNA then returned to control levels after 24 hr. Similar changes were observed when the cells were treated with corticosterone. Pro-opiomelanocortin mRNA was also decreased after dexamethasone pretreatment; however, the time course was much slower with a significant effect only detected after 6 hr. Further analysis of the mechanisms that mediate glucocorticoid regulation of CRF-R1 mRNA was conducted. These studies demonstrated that glucocorticoid incubation significantly decreases the rate of CRF-R1 gene transcription, as determined by nuclear run-on analysis. In addition, the results demonstrate that glucocorticoid incubation significantly decreases CRF-R1 mRNA stability by approximately 50%. The down-regulation of CRF-R1 mRNA was dependent on de novo protein synthesis, as it was blocked by pretreatment with cycloheximide. This represents a novel mechanism for glucocorticoid negative feedback regulation of CRF-R1 expression.Glucocorticoids are known to have a wide array of physiological actions, including cardiovascular, respiratory, immunological, reproductive, and neurobehavioral effects (1, 2). The release of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal axis, and glucocorticoids, in turn, exert a strong, negative feedback effect on this neuroendocrine loop (3-5). Dysfunction of the hypothalamic-pituitary-adrenal axis is associated with and contributes to several psychiatric and endocrine disorders (6, 7), and a great deal of interest has focused on identification of the mechanisms, at the molecular level, that mediate feedback regulation of this neuroendocrine axis.A primary site of action for glucocorticoid negative feedback, in addition to the hypothalamus and hippocampus in brain, are the corticotrophic cells in anterior pituitary (5, 6). Stimulation of these cells by CRF results in the release of ACTH, which provides the principal stimulus for the synthesis and release of glucocorticoids from the adrenal cortex (8). Glucocorticoid negative feedback of corticotrophic cell function occurs at several levels, but the best characterized are the synthesis and release of ACTH (3, 4, 9 -11) and expression of CRF receptors (5, 12, 13). Synthesis of ACTH and its precursor, POMC, is negatively regulated by glucocorticoids (9, 14 -16). This occurs by decreasing the rate of POMC gene transcription (15,17,18). The level of CRF receptors is also decreased by glucocorticoids, but the mechanisms that mediate the down-regulation of these receptors have...

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“…In PVN, stress has been shown to increase gene expression of CRF 1 (33,41,48). Other studies have addressed this issue in pituitary corticotrophs bearing CRH receptors, which are stimulated by CRH to secrete ACTH (1,28,59): CRF 1 expression in pituitary corticotrophs was modulated by stress in a biphasic manner-a reduction at 2 h was followed by an increase at 4 h (47)-raising the possibility of altered receptor turnover. The only published investigation of the regulation of brain CRH receptor mRNA after acute stress found changes in CRH receptor expression that were confined to the hypothalamus (48).…”

Section: Introductionmentioning

confidence: 99%

Corticotropin-Releasing Hormone (CRH) Downregulates the Function of Its Receptor (CRF1) and Induces CRF1 Expression in Hippocampal and Cortical Regions of the Immature Rat Brain

Brunson

Grigoriadis

Lorang

et al. 2002

Experimental Neurology

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In addition to regulating the neuroendocrine stress response, corticotropin-releasing hormone (CRH) has been implicated in both normal and pathological behavioral and cognitive responses to stress. CRH-expressing cells and their target neurons possessing CRH receptors (CRF 1 and CRF 2 ) are distributed throughout the limbic system, but little is known about the regulation of limbic CRH receptor function and expression, including regulation by the peptide itself. Because CRH is released from limbic neuronal terminals during stress, this regulation might play a crucial role in the mechanisms by which stress contributes to human neuropsychiatric conditions such as depression or posttraumatic stress disorder. Therefore, these studies tested the hypothesis that CRH binding to CRF 1 influenced the levels and mRNA expression of this receptor in stress-associated limbic regions of immature rat. Binding capacities and mRNA levels of both CRF 1 and CRF 2 were determined at several time points after central CRH administration. CRH downregulated CRF 1 binding in frontal cortex significantly by 4 h. This transient reduction (no longer evident at 8 h) was associated with rapid increase of CRF 1 mRNA expression, persisting for >8 h. Enhanced CRF 1 expression-with a different time course-occurred also in hippocampal CA3, but not in CA1 or amygdala, CRF 2 binding and mRNA levels were not altered by CRH administration. To address the mechanisms by which CRH regulated CRF 1 , the specific contributions of ligand-receptor interactions and of the CRH-induced neuronal stimulation were examined. Neuronal excitation without occupation of CRF 1 induced by kainic acid, resulted in no change of CRF 1 binding capacity, and in modest induction of CRF 1 mRNA expression. Furthermore, blocking the neuroexcitant effects of CRH (using pentobarbital) abolished the alterations in CRF 1 binding and expression. These results indicate that CRF 1 regulation involves both occupancy of this receptor by its ligand, as well as "downstream" cellular activation and suggest that stress-induced perturbation of CRH-CRF 1 signaling may contribute to abnormal neuronal communication after some stressful situations.

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Regulation of Corticotropin-Releasing Factor (CRF) Receptors in the Rat Pituitary Gland: Effects of Adrenalectomy on CRF Receptors and Corticotroph Responses

Cited by 160 publications

References 45 publications

Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary.

Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary.

Glucocorticoid Regulation of Corticotropin-Releasing Factor₁Receptor Expression in Pituitary-Derived AtT-20 Cells

Corticotropin-Releasing Hormone (CRH) Downregulates the Function of Its Receptor (CRF1) and Induces CRF1 Expression in Hippocampal and Cortical Regions of the Immature Rat Brain

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Regulation of Corticotropin-Releasing Factor (CRF) Receptors in the Rat Pituitary Gland: Effects of Adrenalectomy on CRF Receptors and Corticotroph Responses

Cited by 160 publications

References 45 publications

Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary.

Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary.

Glucocorticoid Regulation of Corticotropin-Releasing Factor1Receptor Expression in Pituitary-Derived AtT-20 Cells

Corticotropin-Releasing Hormone (CRH) Downregulates the Function of Its Receptor (CRF1) and Induces CRF1 Expression in Hippocampal and Cortical Regions of the Immature Rat Brain

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Glucocorticoid Regulation of Corticotropin-Releasing Factor₁Receptor Expression in Pituitary-Derived AtT-20 Cells