Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.661872
Title: Mechanism and modulation of early glucocorticoid inhibition in anterior pituitary corticotrophs
Author: Shipston, Michael J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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Abstract:
Corticotrophin releasing factor (CRF-41) and arginine vasopressin (AVP) are the principal hypothalamic mediators of adrenocorticotrophin (ACTH) secretion by the anterior pituitary gland, while adrenal corticosteroids are the major inhibitors of ACTH output. The aim of this thesis is to characterize in vitro the mechanism and potential modulation of early glucocorticoid inhibition of stimulated ACTH release in anterior pituitary corticotrophs. In perifused rat anterior pituitary corticotrophs early (< 2h) glucocorticoid inhibition of CRF-41- and AVP-stimulated ACTH release was mediated through type II glucocorticoid receptors and the induction of new mRNA and protein. Glucocorticoids inhibited the amount of ACTH released by either secretagogue, but had no effect on the time-course of the ACTH secretory response. Significantly, the characteristics of early glucocorticoid inhibition were dependent on the nature of the secretagogue as well as the relative timing of glucocorticoid application. ACTH secretion stimulated by AVP, that acts through the inositol phosphate/protein kinase C pathway, was invariably suppressed by glucocorticoids. In contrast, CRF-41, that activates the cAMP/protein kinase A pathway, inactivated early glucocorticoid inhibition of CRF-41-, but not AVP-stimulated ACTH release when applied at the start of glucocorticoid exposure. When CRF-41 and AVP were applied in combination the characteristics of early glucocorticoid inhibition resembled those observed using CRF-41 alone. Qualitatively similar results were obtained in the mouse corticotroph cell line, AtT20 D16:16, in static incubation: CRF-41, but not phorbol dibutyrate ester (that activates protein kinase C), blocked early inhibition of CRF-41-stimulated ACTH release. The precise mechanism of CRF-41-inactivation of earlyglucocorticoid inhibition is unknown, however, the time-course of the effectsuggests that CRF-41 blocks glucocorticoid-induced gene transcription. To test this hypothesis and further explore the mechanism(s) of early glucocorticoid inhibition in corticotrophs, the mouse corticotroph cell line, AtT20 D16:16, was used to characterize erly glucocorticoid-induced protein(s).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.661872  DOI: Not available
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