Regulation of adrenocorticotropic hormone secretion from the anterior pituitary gland

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Background: In mammals, the release of corticotropin-releasing hormone (CRH) upon stress stimulates adrenocorticotropic hormone (ACTH) secretion from corticotropes in the pituitary gland. ACTH, in turn, triggers glucocorticoids (GC) secretion from the adrenal gland. GC exerts a rapid (non-genomic) suppression on the CRH-evoked ACTH release. Dysregulation in this rapid phase of GC-mediated feedback was found in adult rodents that were exposed to prenatal stress. Goals and hypotheses: Our short-term goals are to elucidate the cellular mechanisms underlying the rapid negative regulation of pituitary ACTH release, and the cellular adaptations that contribute to the dysregulation of the rapid phase of GC-mediated negative feedback of ACTH release in an animal model of prenatal stress. Our long-term goal is to understand the mechanisms by which ACTH release can be shaped by various types of environmental stressors. Our general hypotheses are: (i) the rapid inhibitory action of GC on ACTH release from corticotropes is mediated via the paracrine actions of two signaling molecules: annexin A1 (AnxA1) and nitric oxide (NO), which are released by the neighboring glial-like pituitary folliculostellate (FS) cells; and (ii) the prenatal stress-induced dysregulation of the rapid phase of GC suppression of ACTH secretion is caused by a decrease in the release of signaling molecules from FS cells and changes in the expression of receptors/ion channels in corticotropes and FS cells. PROJECT 1: Cellular mechanisms underlying the inhibitory actions of AnxA1 and NO on corticotropes By employing corticotropes from POMC-eGFC mice, we shall test the hypothesis that the CRH-evoked depolarization is reversed by: (a) AnxA1, which acts via the formyl peptide receptors (FPR) to reduce a background TRPC current; (b) NO, which enhances the background TREK-1 K+ current and/or suppresses a TRPC current. PROJECT 2: Role of AnxA1 and NO release from FS cells in the rapid inhibitory actions of GC Using confocal imaging on pituitary slices of POMC-eGFP mice, we shall test the hypothesis that the stimulation of GC receptors on FS cells causes the release of AnxA1 and NO which, in turn, acts on neighboring corticotropes to suppress the CRH-evoked Ca2+ signal. PROJECT 3: Impact of prenatal stress on the interactions between FS cells and (ii) there are changes in the expression of FPR, background TRPC or TREK-1 channels in corticotropes. Significance: Our results will unravel the cellular mechanisms underlying the rapid phase of the GC-mediated negative regulation of ACTH release. This knowledge will be a major advance in our general understanding of the physiological regulation of the endocrine response to stress.