Seidel Eric, Scholl Ute I
Department of Nephrology, University Hospital Düsseldorf, Heinrich Heine University , Düsseldorf , Germany.
Front Endocrinol (Lausanne). 2016 Jun 27;7:75. doi: 10.3389/fendo.2016.00075. eCollection 2016.
The adrenal cortex is a major site of steroid hormone production. Two hormones are of particular importance: aldosterone, which is produced in the zona glomerulosa in response to volume depletion and hyperkalemia, and cortisol, which is produced in the zona fasciculata in response to stress. In both cases, acute stimulation leads to increased hormone production, and chronic stimulation causes hyperplasia of the respective zone. Aldosterone- and cortisol-producing adenomas (APAs and CPAs) are benign tumors of the adrenal cortex that cause excess hormone production, leading to primary aldosteronism and Cushing's syndrome, respectively. About 40% of the APAs carry somatic heterozygous gain-of-function mutations in the K(+) channel KCNJ5. These mutations lead to sodium permeability, depolarization, activation of voltage-gated Ca(2+) channels, and Ca(2+) influx. Mutations in the Na(+)/K(+)-ATPase subunit ATP1A1 and the plasma membrane Ca(2+)-ATPase ATP2B3 similarly cause Na(+) or H(+) permeability and depolarization, whereas mutations in the Ca(2+) channel CACNA1D directly lead to increased calcium influx. One in three CPAs carries a recurrent gain-of-function mutation (L206R) in the PRKACA gene, encoding the catalytic subunit of PKA. This mutation causes constitutive PKA activity by abolishing the binding of the inhibitory regulatory subunit to the catalytic subunit. These mutations activate pathways that are relatively specific to the respective cell type (glomerulosa versus fasciculata), and there is little overlap in mutation spectrum between APAs and CPAs, but co-secretion of both hormones can occur. Mutations in CTNNB1 (beta-catenin) and GNAS (Gsα) are exceptions, as they can cause both APAs and CPAs through pathways that are incompletely understood.
肾上腺皮质是类固醇激素产生的主要部位。有两种激素尤为重要：醛固酮，由球状带产生，对容量减少和高钾血症作出反应；皮质醇，由束状带产生，对应激作出反应。在这两种情况下，急性刺激会导致激素产生增加，慢性刺激则会导致相应区域增生。醛固酮瘤和皮质醇瘤是肾上腺皮质的良性肿瘤，分别导致醛固酮分泌过多和库欣综合征。约40%的醛固酮瘤在钾离子通道KCNJ5中携带体细胞杂合功能获得性突变。这些突变导致钠通透性增加、去极化、电压门控钙通道激活以及钙离子内流。钠离子/钾离子-ATP酶亚基ATP1A1和质膜钙ATP酶ATP2B3中的突变同样会导致钠或氢通透性增加和去极化，而钙通道CACNA1D中的突变则直接导致钙离子内流增加。三分之一的皮质醇瘤在编码蛋白激酶A催化亚基的PRKACA基因中携带复发性功能获得性突变（L206R）。该突变通过消除抑制性调节亚基与催化亚基的结合导致蛋白激酶A持续激活。这些突变激活了相对特定于各自细胞类型（球状带与束状带）的信号通路，醛固酮瘤和皮质醇瘤的突变谱几乎没有重叠，但两种激素可同时分泌。CTNNB1（β-连环蛋白）和GNAS（Gsα）中的突变是例外，因为它们可通过尚未完全了解的信号通路导致醛固酮瘤和皮质醇瘤。
