Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function

Willenberg, Holger S.; Bornstein, Stefan R.; Hiroi, Naoki; Päth, G; Goretzki, P. E.; Scherbaum, Werner A.; Chrousos, George P.

doi:10.1038/sj.mp.4000720

Cited by 53 publications

(40 citation statements)

References 47 publications

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“…31 This confirms previous reports demonstrating a local CRH/ACTH system in the adrenal medulla. Thus, CRH was shown to stimulate cortisol production in cortical and chromaffin cell co-cultures.…”

Section: Discussionsupporting

confidence: 82%

Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls

et al. 2001

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Corticotropin-releasing hormone (CRH) is a key neuroendocrine factor implementing endocrine, immune and behavioral responses to stress. CRH exerts its action through two major receptors, CRH-R1 and CRH-R2. Recently novel non-peptidic antagonists directed against CRH-R1 or CRH-R2 have been proposed as promising agents in the treatment of depression, anxiety and eating disorder. However, so far the CRH-receptor system has not been widely studied in humans. Therefore, we employed quantitative TaqMan PCR to analyze the expression and distribution of both CRH-R1 and CRH-R2 in human brain tissue and peripheral organs. Furthermore the expression of CRH receptors was analyzed for the first time in pituitaries of suicide victims by in situ hybridization and quantitative PCR. Our data demonstrated a different expression pattern in humans as compared to rodents. Both CRH-R1 and CRH-R2 were expressed in high amounts in the brain with the strongest expression in the pituitary. As described in rodents, however the CRH-R1 in human was the predominant receptor in the brain (82.7 ± 11.0%), whilst CRH-R2 was the predominant receptor in peripheral organs (77.0 ± 15.8%). There was a shift in the ratio of CRH-R1/R2 in the pituitaries of suicide victims. In conclusion, both CRH-R1 and CRH-R2 are widely expressed in human tissues with a distribution substantially different from rodents. Strong expression of both CRH-R1 and CRH-R2 in human pituitaries suggests that particularly under stress, activation of the HPA axis can be maintained through both receptors. Molecular Psychiatry (2001) 6, 540-546.

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Section: Discussionsupporting

confidence: 82%

Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls

et al. 2001

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“…These direct effects of CRF on the adrenal gland require the local presence of CRF receptors. Indeed, CRF receptors, predominantly CRF receptor 1 (CRF-R1), are found within the adrenal gland (Dave et al 1985, Udelsman et al 1986, Aguilera et al 1987, Willenberg et al 2000, Muller et al 2001. In addition, CRF-binding protein (CRF-BP), an important modulator of the concentration of free bioavailable CRF, has also been demonstrated in chromaffin cells of rat adrenal gland (Chatzaki et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Corticotropin-releasing factor (CRF) and CRF-binding protein expression in and release from the head kidney of common carp: evolutionary conservation of the adrenal CRF system

Huising

Metz

et al. 2007

Journal of Endocrinology

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Corticotropin-releasing factor (CRF) plays a central role in the regulation of the stress axis. In mammals, CRF as well as its receptors and its CRF-binding protein (CRF-BP) are expressed in a variety of organs and tissues outside the central nervous system. One of these extrahypothalamic sites is the adrenal gland, where the paracrine actions of adrenal CRF influence cortical steroidogenesis and adrenal blood flow. Although the central role of CRF signaling in the initiation and regulation of the stress response has now been established throughout vertebrates, information about the possible peripheral presence of CRF in earlier vertebrate lineages is scant. We established the expression of CRF, CRF-BP, and the CRF receptor 1 in a panel of peripheral organs of common carp (Cyprinus carpio). Out of all the peripheral organs tested, CRF and CRF-BP are most abundantly expressed in the carp head kidney, the fish equivalent of the mammalian adrenal gland. This expression localizes to chromaffin cells. Furthermore, detectable quantities of CRF are released from the intact head kidney following in vitro stimulation with 8-bromo-cAMP in a superfusion setup. The presence of CRF and CRF-BP within the chromaffin compartment of the head kidney suggests that a pathway homologous to the mammalian intraadrenal CRF system is present in the head kidney of fish. It follows that such a system to locally fine-tune the outcome of the centrally initiated stress response has been an integral part of the vertebrate endocrine system since the common ancestor of teleostean fishes and mammals.

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“…Chromaffin cells express CRHR1 receptors and there is an intraadrenal CRH/ACTH system under feedback control of glucocorticoids. 12,19 Exogenous CRH preserves chromaffin cell morphology in vitro and stimulates catecholamine production in dispersed rat chromaffin and human pheochromocytoma cells. 21 Hypoxia-induced adrenal chromaffin cell changes are partially reversed with exogenous CRH.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

“…[16][17][18] Recent studies demonstrated low epinephrine levels and a decrease in adrenal PNMT expression in CRH-deficient mice 4,6,7 and adrenomedullary atrophy has been reported in CRHR1 null mice. 6 CRHR1 receptors are expressed on chromaffin cells 19 and a direct action of CRH on chromaffin cell function has been described. 20,21 CRHR1 null mice are an interesting model to analyze the role of the CRH system for the functioning of the adrenal medulla.…”

Section: Introductionmentioning

confidence: 99%

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

et al. 2002

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Corticotropin-releasing hormone (CRH) is both a main regulator of the hypothalamic-pituitaryadrenocortical axis and the autonomic nervous system. CRH receptor type 1 (CRHR1)-deficient mice demonstrate alterations in behavior, impaired stress responses with adrenocortical insufficiency and aberrant neuroendocrine development, but the adrenal medulla has not been analyzed in these animals. Therefore we studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides and the ultrastructure of chromaffin cells in CRHR1 null mice. In addition we examined whether treatment of CRHR1 null mice with adrenocorticotropic hormone (ACTH) could restore function of the adrenal medulla. CRHR1 null mice received saline or ACTH, and wildtype or heterozygous mice injected with saline served as controls. Adrenal epinephrine levels in saline-treated CRHR1 null mice were 44% those of controls (P Ͻ0.001), and the phenylethanolamine N-methyltransferase (PNMT) mRNA levels in CRHR1 null mice were only 25% of controls (P Ͻ0.001). ACTH treatment increased epinephrine and PNMT mRNA level in CRHR1 null mice but failed to restore them to normal levels. Proenkephalin mRNA in both saline-and ACTH-treated CRHR1 null mice were higher than in control animals (215.8% P Ͻ0.05, 268.9% P Ͻ0.01) whereas expression of neuropeptide Y and chromogranin B did not differ. On the ultrastructural level, chromaffin cells in saline-treated CRHR1 null mice exhibited a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. In conclusion, CRHR1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine biosynthesis. Molecular Psychiatry (2002) 7, 967-974.

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Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function

Abstract: Corticotropin-releasing hormone (CRH) is

Cited by 53 publications

References 47 publications

Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls

Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls

Corticotropin-releasing factor (CRF) and CRF-binding protein expression in and release from the head kidney of common carp: evolutionary conservation of the adrenal CRF system

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

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