The expression of the ACTH receptor

Abstract

Adrenal glucocorticoid secretion is regulated by adrenocorticotropic hormone (ACTH) acting through a specific cell membrane receptor (ACTH-R). The ACTH-R is a member of the G protein superfamilycoupled receptors and belongs to the subfamily of melanocortin receptors. The ACTH-R is mainly expressed in the adrenocortical cells showing a restricted tissue specificity, although ACTH is recognized by the other four melanocortin receptors. The cloning of the ACTH-R was followed by the study of this gene in human diseases such as familial glucocorticoid deficiency (FGD) and adrenocortical tumors. FGD is a rare autosomal recessive disease characterized by glucocorticoid deficiency, elevated plasma ACTH levels and preserved renin/ aldosterone secretion. This disorder has been ascribed to an impaired adrenal responsiveness to ACTH due to a defective ACTH-R, a defect in intracellular signal transduction or an abnormality in adrenal cortical development. Mutations of the ACTH-R have been described in patients with FGD in segregation with the disease. The functional characterization of these mutations has been prevented by difficulties in expressing human ACTH-R in cells that lack endogenous melanocortin receptor activity. To overcome these difficulties we used Y6 cells, a mutant variant of the Y1 cell line, which possesses a nonexpressed ACTH-R gene allowing the functional study without any background activity. Our results demonstrated that the several mutations of the ACTH-R found in FGD result in an impaired cAMP response or loss of sensitivity to ACTH stimulation. An ACTHbinding study showed an impairment of ligand binding with loss of the high affinity site in most of the mutations studied.

Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsα in juxtaglomerular cells

“…The reduction of plasma aldosterone in the RC/FF mice is probably a consequence of the greatly reduced plasma renin and consequent reduction in angiotensin II signaling. However, since certain signaling pathways in the zona glomerulosa involve cAMP, for example, that is activated by ACTH, we cannot exclude that a reduction of Gs␣ expression in the adrenal gland contributes to this effect (8). Previous studies have shown that a reduction of angiotensin II signaling by angiotensin-converting enzyme or angiotensin receptor blockade or genetic deletion of components of the reninangiotensin system causes a consistent upregulation of COX-2 in MD and TAL cells (6,7,14,34,35).…”

Analysis of Single Nucleotide Polymorphisms in the Melanocortin-4 Receptor Promoter in Infantile Spasms

“…MC2R is a member of the G protein coupled superfamily receptors and belongs to the melanocortin receptor family [54 ] . MC2R is mainly expressed in the adrenocortical cells, shows a low expression in skin and adipose tissue, while the pituitary and hypothalamus do not express MC2R [18 ] . In the HPA axis, CRH promotes the release of pituitary ACTH, ACTH circulates to the adrenal cortex where it binds to MC2R.…”

In vitro culture on Matrigel favors the long-term maintenance of rat zona glomerulosa-cell differentiated phenotype

“…The baseline 180-min production of both ALDO and 18OH-CORT is markedly higher at day 6 than at day 3 of growth on Matrigel; and iii) Matrigel culture favors the maintenance of the expression of either ACTH and Ang-II receptors or voltage-gated Ca 2+ channels in ZG cells. The steroidogenic effects of ACTH and Ang-II are mediated by the MC2 (27,28) and the AT1 receptors (29), while K + depolarizes the cell plasma membrane with the ensuing opening of L-type Ca 2+ channels (30,31). Tissue culture on plastic causes a time-dependent decrease in the secretory response of ZG cells to all their main agonists, while the growth on Matrigel maintains higher the response to ACTH and Ang-II and unchanged that to K + .…”