The expression of the ACTH receptor

Adrenal glucocorticoid secretion is regulated by adrenocorticotropic hormon e (ACTH) acting through a specific cell membrane receptor (ACTH-R). The ACT H-R is a member of the G protein superfamily coupled receptors and belongs to the subfamily of melanocortin receptors. The ACTH-R is mainly expressed in the adrenocortical cells showing a restricted tissue specificity, althou gh 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 suc h as familial glucocorticoid deficiency (FGD) and adrenocortical tumors. FG D is a ran autosomal recessive disease characterized by,glucocorticoid defi ciency, elevated plasma ACTH levels and preserved renin/aldosterone secreti on. This disorder has been ascribed to an impaired adrenal responsiveness t o ACTH due to a defective ACTH-R, a defect in intracellular signal transduc tion or an abnormality in adrenal cortical development. Mutations of the AC TH-R have been described in patients with FGD in segregation with the disea se. The functional characterization of these mutations has been prevented b y difficulties in expressing human ACTH-R in cells that lack endogenous mel anocortin receptor activity. To overcome these difficulties we used Y6 cell s, a mutant variant of the YI cell line, which possesses a nonexpressed ACT H-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 stimula tion. An ACTH-binding study showed an impairment of ligand binding with los s of the high affinity site in most of the mutations studied.