ADRENOCORTICOTROPIN RECEPTOR AND ADRENAL DISORDERS

The ACTH receptor is the shortest G-protein-coupled receptor to date a nd consists of 297 residues with two putative glycosylation sites at t he extracellular N terminus. In vitro studies have demonstrated upregu lation of the ACTH receptor by its own ligand and by angiotensin II. I nactivating mutations of the ACTH receptor lead to the familial glucoc orticoid deficiency (FGD) syndrome, a rare recessive autosomal disorde r characterized by degeneration of the zona fasciculata/reticularis an d unresponsiveness to exogenous ACTH. Interestingly, ACTH receptor mut ations are not present in all patients with FGD and also not in the cl osely related 'triple A' syndrome indicating that other mechanisms of ACTH resistance are still to be elucidated. Despite an extensive searc h, no activating ACTH receptor mutations have been found in adrenal tu mors, excluding the ACTH receptor as a relevant oncogene for adrenal t umorigenesis. However, the ACTH receptor may play a role as a differen tiation factor, as loss of heterozygosity for the ACTH receptor in adr enal tumors seems to be associated with an undifferentiated phenotype. ACTH receptor mRNA expression in benign adrenal tumors is strongly re lated to the expression of P-450 side chain cleavage enzyme mRNA indic ating a close regulative relationship. However, this correlation is di srupted in adrenal carcinomas, an observation which may help in the di fficult differential diagnosis between benign and malignant tumors. Su rprisingly, the highest ACTH receptor mRNA expression was found in ald osteronomas, while it is low in nonfunctioning adenomas and carcinomas . No correlation between ACTH receptor mRNA expression and circulating ACTH levels has been found in patients with adrenal disorders casting doubts on the physiological significance of ACTH receptor upregulatio n by its own ligand in vivo.