Department of Endocrinology and Medical Sciences, University of Genova, Genova, Italy.
Neuroendocrinology. 2010;92 Suppl 1:17-22. doi: 10.1159/000314293. Epub 2010 Sep 10.
The recent depiction of dopamine receptors (DRs) in tumors that cause Cushing's syndrome (CS) has renewed the debate about the dopamine control on pituitary-adrenal axis, and opened interesting new perspectives for medical treatment of CS. The new insights arise from the recent accurate characterization of DR subtypes expression within tumors causing CS, the discovery of new mechanisms, such as the dimerization between DRs and other G-protein coupled receptors (CPCRs), including somatostatin receptors (SSTRs), and the recent availability of new agents targeting these receptor subtypes. Corticotropic adenomas express DR subtype 2 (D(2)R), together with different SSTR subtypes (ssts), in particular sst(5). In vitro, activation of D(2)R inhibits ACTH release in the majority of cultures of corticotropic cells, whereas, in vivo, dopaminergic agents display an inhibitory effect on cortisol levels in a subset of patients with CS. In animal models the receptor profile can be deeply modulated in specific environmental conditions, that may resemble the different clinical phases of CS. The new insights about DRs and receptor-targeting drugs may offer different approaches for medical treatment of CS: combination therapies with different types of compounds, treatment with novel molecules (hybrid compounds) with a wider spectrum of activity, or even pretreatment manipulation of receptor profile. Finally, recent studies showed that D(2)R is also significantly expressed in ectopic ACTH-secreting tumors and in both normal and tumoral adrenal tissues. Dopamine-agonists may decrease cortisol levels in a number of these patients, strengthening the current (re)emerging interest in DRs as possible targets for medical treatment of CS.
最近在引起库欣综合征（CS）的肿瘤中对多巴胺受体（DRs）的描述，重新引发了关于多巴胺对垂体-肾上腺轴控制的争论，并为 CS 的医学治疗开辟了有趣的新视角。这些新的见解源于最近对引起 CS 的肿瘤中 DR 亚型表达的准确特征描述，新机制的发现，例如 DR 与其他 G 蛋白偶联受体（CPCRs），包括生长抑素受体（SSTRs）之间的二聚化，以及最近出现的针对这些受体亚型的新药物。促皮质腺瘤表达 DR 亚型 2（D2R），以及不同的 SSTR 亚型（ssts），特别是 sst（5）。在体外，D2R 的激活抑制大多数促皮质细胞培养物中 ACTH 的释放，而在体内，多巴胺能药物在 CS 患者的亚组中显示出对皮质醇水平的抑制作用。在动物模型中，受体谱可以在特定的环境条件下被深度调节，这些条件可能类似于 CS 的不同临床阶段。关于 DR 和受体靶向药物的新见解可能为 CS 的医学治疗提供不同的方法：不同类型化合物的联合治疗，使用具有更广泛活性的新型分子（杂交化合物）进行治疗，甚至是受体谱的预处理操作。最后，最近的研究表明，D2R 在异位 ACTH 分泌肿瘤以及正常和肿瘤肾上腺组织中也有明显表达。多巴胺激动剂可能会降低许多这些患者的皮质醇水平，这加强了目前（重新）出现的将 DR 作为 CS 医学治疗的可能靶点的兴趣。
