ADRENOCORTICOTROPIC HORMONE (ACTH) INCREASES THE EXPRESSION OF ITS OWN RECEPTOR GENE

Regulation of the ACTH receptor (R) in the adrenal gland by its own li gand ''ACTH'' has been a matter of controversy. In the present study, whether ACTH regulates the expression of mRNA for its own receptor in the adrenal gland was studied in human subjects and in rats in vivo. I n the human study, adrenal adenoma tissues as well as adjacent normal tissues were obtained at surgery from two patients with typical Gushin g's syndrome. Northern blot analysis revealed two ACTH-R mRNA species with 4.0 kb and 2.0 kb. ACTH-R mRNAs in the adenoma tissues were much more abundant than those in the normal tissues from the two patients, suggesting that the mRNA in normal adrenal tissue is either suppressed by cortisol excess or the absence of ACTH. To examine the mechanism i nvolved in ACTH-R mRNA regulation, the changes in the receptor mRNA ca used by ACTH were studied in dexamethasone-treated rats. Administratio n of dexamethasone for 5 days resulted in a marked decrease in ACTH-R mRNA to an undetectable level. A bolus administration of ACTH(1-24) in travenously or ACTH-Z(1-24) intramuscularly to the dexamethasone-treat ed rat did not cause any significant change in ACTH-R mRNA from 0.5 to 12 h after the administration. However, a significant increase in the receptor mRNA was observed at 24 h after the ACTH-Z(1-24) and the lev el was further increased until 48 h followed by a sustained increase a t 72 h when it was given once every 24 h. These data suggest that the ACTH-receptor is increased by ACTH at a pretranslational level. Althou gh it remains to be studied whether the increased receptor mRNA level in the adenoma tissues of the patients with Cushing's syndrome is a ge neral phenomenon, the results suggest that the regulatory mechanism of the receptor in the adenoma is different from that in normal tissue a nd this could contribute to the pathogenesis of autonomous production of cortisol.