THE ACTH RECEPTOR AND DISORDERS OF ADRENOCORTICAL FUNCTIONS

The adrenocorticotropin (ACTH) receptor is one of the smallest of the G-protein-coupled receptors and consists of 297 residues with two puta tive glycosylation sites on the extracellular N terminus. The ACTH rec eptor, a key element of the hypothalamic pituitary axis influencing th e responsiveness of adrenocortical cells to stimulation, shows an unus ual ''upregulation'' by its own ligand. Inactivating mutations of the ACTH receptor lead to the familial glucocorticoid deficiency (FGD) syn drome, a rare recessive autosomal disorder characterized by degenerati on of the zona fasciculata/reticularis and unresponsiveness to exogeno us ACTH, Interestingly, ACTH receptor mutations are not present in all patients with FGD and also are not in the closely related ''triple A' ' syndrome, indicating that other mechanisms of ACTH resistance are st ill to be found. Despite an extensive search, no activating ACTH recep tor mutations have been found in adrenal tumors, excluding the ACTH re ceptor as a relevant oncogene for adrenal tumorigenesis. The ACTH rece ptor, however, may play a role as a differentiation factor because los s of heterozygosity for the ACTH receptor in adrenal tumors seems to b e associated with an undifferentiated phenotype, ACTH receptor mRNA ex pression in benign adrenal tumors is related strongly to the expressio n of P450 steroidogenic enzyme mRNA, indicating a close regulative rel ationship Adrenocortical carcinomas express ACTH receptor mRNA transcr ipts, although generally at low levels. ''Downregulation'' of ACTH rec eptor expression in normal and neoplastic tissue can be achieved by ad renostatic compounds such as aminoglutethimide and metyrapone, This ma y be useful in some patients with adrenal pathology.