Allolio B, Reincke M
Schwerpunkt Endokrinologie, Medizinische Universitätsklinik, Würzburg, Deutschland.
Horm Res. 1997;47(4-6):273-8. doi: 10.1159/000185476.
The ACTH receptor is the shortest G-protein-coupled receptor to date and consists of 297 residues with two putative glycosylation sites at the extracellular N terminus. In vitro studies have demonstrated upregulation of the ACTH receptor by its own ligand and by angiotensin II. Inactivating mutations of the ACTH receptor lead to the familial glucocorticoid deficiency (FGD) syndrome, a rare recessive autosomal disorder characterized by degeneration of the zona fasciculata/reticularis and unresponsiveness to exogenous ACTH. Interestingly, ACTH receptor mutations are not present in all patients with FGD and also not in the closely related "triple A' syndrome indicating that other mechanisms of ACTH resistance are still to be elucidated. Despite an extensive search, no activating ACTH receptor mutations have been found in adrenal tumors, excluding the ACTH receptor as a relevant oncogene for adrenal tumorigenesis. However, the ACTH receptor may play a role as a differentiation factor, as loss of heterozygosity for the ACTH receptor in adrenal tumors seems to be associated with an undifferentiated phenotype. ACTH receptor mRNA expression in benign adrenal tumors is strongly related to the expression of P-450 side chain cleavage enzyme mRNA indicating a close regulative relationship. However, this correlation is disrupted in adrenal carcinomas, an observation which may help in the difficult differential diagnosis between benign and malignant tumors. Surprisingly, the highest ACTH receptor mRNA expression was found in aldosteronomas, while it is low in non-functioning 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 upregulation by its own ligand in vivo.
促肾上腺皮质激素（ACTH）受体是迄今为止最短的G蛋白偶联受体，由297个氨基酸残基组成，在细胞外N端有两个假定的糖基化位点。体外研究表明，其自身配体和血管紧张素II可使ACTH受体上调。ACTH受体的失活突变会导致家族性糖皮质激素缺乏（FGD）综合征，这是一种罕见的常染色体隐性疾病，其特征为束状带/网状带退化以及对外源性ACTH无反应。有趣的是，并非所有FGD患者都存在ACTH受体突变，与之密切相关的“三A”综合征患者也没有，这表明ACTH抵抗的其他机制仍有待阐明。尽管进行了广泛研究，但在肾上腺肿瘤中未发现激活型ACTH受体突变，排除了ACTH受体作为肾上腺肿瘤发生相关癌基因的可能性。然而，ACTH受体可能作为一种分化因子发挥作用，因为肾上腺肿瘤中ACTH受体杂合性缺失似乎与未分化表型相关。良性肾上腺肿瘤中ACTH受体mRNA表达与P - 450侧链裂解酶mRNA表达密切相关，表明存在紧密的调节关系。然而，这种相关性在肾上腺皮质癌中被破坏，这一观察结果可能有助于肾上腺良恶性肿瘤的困难鉴别诊断。令人惊讶的是，醛固酮瘤中ACTH受体mRNA表达最高，而非功能性腺瘤和癌中表达较低。在肾上腺疾病患者中，未发现ACTH受体mRNA表达与循环ACTH水平之间存在相关性，这使人对其自身配体在体内上调ACTH受体的生理意义产生怀疑。
