Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

Prostaglandin F2α (PGF2α), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF2α synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF2α biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF2α but expressed different biosynthetic isozymes. In chromaffin cells, PGF2α secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF2α secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF2α release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF2α receptor was only detected in chromaffin cells, making medulla the primary target of PGF2α action. By comparing PGF2α-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF2α repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF2α may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal

Long-Term Control of Hypercortisolism by Vandetanib in a Case of Medullary Thyroid Carcinoma with a Somatic RET Mutation

International audienceMedullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies

Implication de l'activite electrique des cellules melanotropes de grenouille dans les processus de couplage stimulus-secretion : etude par la technique de patch-clamp

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Effets du PACAP et du VIP sur la différenciation neuronale des cellules souches embryonnaires de souris

ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Rôle des mastocytes dans l’hyperaldostéronisme primaire

En partenariat avec Les Centres de Référence labellisés pour ces maladies, la filière Maladies Rares Endocriniennes Firendo et avec le parrainage de la SFE et de la SFEDP.International audienc

Contrôle neurotensinergique des cellules mélanotropes de l'hypophyse de grenouille (caractérisation pharmacologique des récepteurs et étude du mécanisme de transduction)

La neurotensine (NT) est un neuropeptide localisé dans le complexe hypothalamo-hypophysaire. La NT stimule les activités électrique et sécrétrice des cellules mélanotropes de grenouille en activant des récepteurs couplés aux protéines Gq/11 et présentant des caractéristiques pharmacologiques intermédiaires entre celles des récepteurs NTR1 et NTR2 de mammifères. L'activation de ces récepteurs stimule la formation d'inositol trisphosphate induisant une mobilisation du Ca2+ des compartiments intracellulaires. L'élévation de la concentration du Ca2+ cytosolique provoque la sécrétion de l'hormone mélanotrope a, l'émission d'un courant chlore responsable d'une dépolarisation membranaire à l'origine de la genèse de potentiels d'action, l'activation de la PKC qui réduit l'amplitude des courants calciques de types L et N ainsi que la genèse d'un courant potassique activé par le Ca2+ impliqué dans les post-potentiels hyperpolarisants nécessaires au maintien de l'excitabilité des cellules.Neurotensin (NT) is a tridecapeptide present in the hypothalamic-pituitary complex. NT stimulates both the electrical and secretory activities of frog melanotrophs via activationt of Gq/11 protein-coupled receptors whose pharmacological profile exhibits similarities with those of mammalian NTR1 and NTR2. Activation of receptors stimulates inositol trisphosphate production that induces a Ca2+ mobilization from intracellular stores. Increase in cytosolic Ca2+ concentration provokes release of a-melanocyte stimulating hormone, chloride efflux through Ca2+-sensitive Cl- channels inducing membrane depolarization and consecutive action potential discharge, activation of PKC that reduces the L- and N-type Ca2+ currents and genesis of calcium-sensitive potassium current involved in hyperpolarizing post-potentials necessary to maintain the cell excitability.ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Rôle des mastocytes dans l’hyperaldostéronisme primaire

En partenariat avec Les Centres de Référence labellisés pour ces maladies, la filière Maladies Rares Endocriniennes Firendo et avec le parrainage de la SFE et de la SFEDP.International audienc

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

International audienceA wide variety of autocrine/paracrine bioactive signals are able to modulate corticosteroid secretion in the human adrenal gland. These regulatory factors, released in the vicinity of adrenocortical cells by diverse cell types comprising chromaffin cells, nerve terminals, cells of the immune system, endothelial cells, and adipocytes, include neuropeptides, biogenic amines, and cytokines. A growing body of evidence now suggests that paracrine mechanisms may also play an important role in the physiopathology of adrenocortical hyperplasias and tumors responsible for primary adrenal steroid excess. These intra-adrenal regulatory systems, although globally involving the same actors as those observed in the normal gland, display alterations at different levels, which reinforce the capacity of paracrine factors to stimulate the activity of adrenocortical cells. The main modifications in the adrenal local control systems reported by now include hyperplasia of cells producing the paracrine factors and abnormal expression of the latter and their receptors. Because steroid-secreting adrenal neoplasms are independent of the classical endocrine regulatory factors angiotensin II and ACTH, which are respectively suppressed by hyperaldosteronism and hypercortisolism, these lesions have long been considered as autonomous tissues. However, the presence of stimulatory substances within the neoplastic tissues suggests that steroid hypersecretion is driven by autocrine/paracrine loops that should be regarded as promising targets for pharmacological treatments of primary adrenal disorders. This new potential therapeutic approach may constitute an alternative to surgical removal of the lesions that is classically recommended in order to cure steroid excess

Rôle de la sérotonine dans la physiopathologie de l’adénome de Conn

International audienc