Constitutive activities in the thyrotropin receptor: regulation and significance.
Constitutive activities in the thyrotropin receptor: regulation and significance.
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DOI：
10.1016/b978-0-12-417197-8.00003-1
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Biebermann, Heike
中科院分区：
文献类型：
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作者：
Kleinau, Gunnar;Biebermann, Heike
促甲状腺激素受体（TSHR 或促甲状腺素受体）是 A 家族 G 蛋白偶联受体。它不仅与促甲状腺激素（TSH 或促甲状腺素）结合，而且在病理条件下与自身抗体相互作用。 TSHR 和 TSH 对于甲状腺生长和功能至关重要，因此对于所有甲状腺激素相关的生理高级过程（包括中枢神经系统的新陈代谢和发育）至关重要。体外研究发现，TSHR 永久刺激 Gs 的配体独立（组成型）激活，最终导致细胞内 cAMP 积累。此外，据报道，TSHR 的多种组成型激活突变（超过 50 个不同的氨基酸位置）可增强基础信号传导。这些在体内导致非自身免疫性甲状腺功能亢进症或毒性腺瘤的“功能获得”表型。此外，已知许多自然发生的失活突变会导致“功能丧失”表型，从而导致对甲状腺激素或高促甲状腺素血症的抵抗。其中一些突变的特征还在于基础信号传导受损，这些突变在此被称为“组成型失活突变”(CIM)。迄今为止，已鉴定出 30 多个具有 CIM 的氨基酸位置。此外，永久性 TSHR 信号传导能力也可以被反向激动抗体或类药物小分子阻断，这两种药物都具有临床应用的潜力。本章描述了 TSHR 组成活性的信息，包括上调和下调、相关蛋白质构象、生理和病理生理条件以及相关的细胞内信号传导。
The thyroid-stimulating hormone receptor (TSHR, or thyrotropin receptor) is a family A G protein-coupled receptor. It not only binds thyroid-stimulating hormone (TSH, or thyrotropin) but also interacts with autoantibodies under pathological conditions. The TSHR and TSH are essential for thyroid growth and function and thus for all thyroid hormone-associated physiological superordinated processes, including metabolism and development of the central nervous system. In vitro studies have found that the TSHR permanently stimulates ligand-independent (constitutive) activation of Gs, which ultimately leads to intracellular cAMP accumulation. Furthermore, a vast variety of constitutively activating mutations of TSHR-at more than 50 different amino acid positions-have been reported to enhance basal signaling. These lead in vivo to a "gain-of-function" phenotype of nonautoimmune hyperthyroidism or toxic adenomas. Moreover, many naturally occurring inactivating mutations are known to cause a "loss-of-function" phenotype, resulting in resistance to thyroid hormone or hyperthyrotropinemia. Several of these mutations are also characterized by impaired basal signaling, and these are designated here as "constitutively inactivating mutations" (CIMs). More than 30 amino acid positions with CIMs have been identified so far. Moreover, the permanent TSHR signaling capacity can also be blocked by inverse agonistic antibodies or small drug-like molecules, which both have a potential for clinical usage. In this chapter, information on constitutive activity in the TSHR is described, including up- and downregulation, linked protein conformations, physiological and pathophysiological conditions, and related intracellular signaling.