Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research and the Monash University, Department of Molecular Translational Science, Clayton, Victoria 3168, Australia.
Departamento de Endocrinologia, Facultad de Medicina, and Centro Traslacional de Endocrinología (CETREN UC) Pontificia, Universidad Catolica de Chile, Santiago, Chile.
Steroids. 2022 Aug;184:109037. doi: 10.1016/j.steroids.2022.109037. Epub 2022 Apr 13.
Cortisol resistance has also been reported in the degu, Octodon degus, a New World hystricomorph endemic to central Chile. The degu is used as a model for studies of stress and diurnal rhythms, parental behaviour and female masculinization. Another New World hystricomorph, the guinea pig, also exhibits glucocorticoid resistance, a result of amino acid sequences that differ from other mammalian glucocorticoid receptors (GR). Mutations in the ligand-binding domain of the human GR have been identified in familial or sporadic generalised cortisol resistance as have variants in the guinea pig. To address the possibility that the high levels of cortisol observed in the degu are a result of the same or similar sequence variations observed in the guinea pig GR, we have cloned, expressed and characterised the ligand-binding domain (LBD) of the degu GR. Somewhat unexpectedly, neither the amino acids nor the region involved in the resistance observed in the guinea pig GR are relevant in the degu GR. The relative resistance to cortisol observed in the degu GR is conferred by the substitution of two isoleucine residues, which are highly conserved in the GR across species, with a valine doublet. These amino acids lie in the region between helices 5 and 6 of the GR LBD, a region known to be important in determining the affinity of ligand-binding in steroid receptors.
皮质醇抵抗也在智利中部特有新世界鳞尾松鼠科的毛丝鼠中被报道。毛丝鼠被用作研究应激和昼夜节律、亲代行为和雌性雄性化的模型。另一种新世界鳞尾松鼠科动物豚鼠也表现出糖皮质激素抵抗，这是由于其氨基酸序列与其他哺乳动物糖皮质激素受体（GR）不同。在家族性或散发性全身性皮质醇抵抗中已经鉴定出人类 GR 配体结合域中的突变，以及豚鼠中的变体。为了解决在毛丝鼠中观察到的高皮质醇水平是否是由于与豚鼠 GR 中观察到的相同或相似的序列变异的结果，我们已经克隆、表达和表征了毛丝鼠 GR 的配体结合域（LBD）。有点出人意料的是，在豚鼠 GR 中观察到的抗性所涉及的氨基酸和区域与毛丝鼠 GR 无关。在毛丝鼠 GR 中观察到的相对皮质醇抵抗是由两个异亮氨酸残基的取代赋予的，这两个残基在跨物种的 GR 中高度保守，被一个缬氨酸二联体取代。这些氨基酸位于 GR LBD 的 5 号和 6 号螺旋之间的区域，该区域已知在决定甾体受体配体结合亲和力方面很重要。
