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恢复下丘脑-垂体-性腺轴中失活的 G 蛋白偶联受体变体的功能。

Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic-pituitary-gonadal axis.

机构信息

Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.

Department of Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.

出版信息

J Neuroendocrinol. 2024 Sep;36(9):e13418. doi: 10.1111/jne.13418. Epub 2024 Jun 9.

Abstract

G protein-coupled receptors (GPCRs) are central to the functioning of the hypothalamic-pituitary-gonadal axis (HPG axis) and include the rhodopsin-like GPCR family members, neurokinin 3 receptor, kappa-opioid receptor, kisspeptin 1 receptor, gonadotropin-releasing hormone receptor, and the gonadotropin receptors, luteinizing hormone/choriogonadotropin receptor and follicle-stimulating hormone receptor. Unsurprisingly, inactivating variants of these receptors have been implicated in a spectrum of reproductive phenotypes, including failure to undergo puberty, and infertility. Clinical induction of puberty in patients harbouring such variants is possible, but restoration of fertility is not always a realisable outcome, particularly for those patients suffering from primary hypogonadism. Thus, novel pharmaceuticals and/or a fundamental change in approach to treating these patients are required. The increasing wealth of data describing the effects of coding-region genetic variants on GPCR function has highlighted that the majority appear to be dysfunctional as a result of misfolding of the encoded receptor protein, which, in turn, results in impaired receptor trafficking through the secretory pathway to the cell surface. As such, these intracellularly retained receptors may be amenable to 'rescue' using a pharmacological chaperone (PC)-based approach. PCs are small, cell permeant molecules hypothesised to interact with misfolded intracellularly retained proteins, stabilising their folding and promoting their trafficking through the secretory pathway. In support of the use of this approach as a viable therapeutic option, it has been observed that many rescued variant GPCRs retain at least a degree of functionality when 'rescued' to the cell surface. In this review, we examine the GPCR PC research landscape, focussing on the rescue of inactivating variant GPCRs with important roles in the HPG axis, and describe what is known regarding the mechanisms by which PCs restore trafficking and function. We also discuss some of the merits and obstacles associated with taking this approach forward into a clinical setting.

摘要

G 蛋白偶联受体(GPCRs)是下丘脑-垂体-性腺轴(HPG 轴)功能的核心,包括视紫红质样 GPCR 家族成员、神经激肽 3 受体、κ-阿片受体、促性腺激素释放激素受体、促性腺激素受体、促黄体生成素/绒毛膜促性腺激素受体和卵泡刺激素受体。毫不奇怪,这些受体的失活变体与一系列生殖表型有关,包括青春期发育失败和不育。在携带这些变体的患者中临床诱导青春期是可能的,但生育力的恢复并不总是可行的结果,特别是对于那些患有原发性性腺功能减退症的患者。因此,需要新型药物和/或治疗这些患者的方法的根本改变。描述编码区遗传变异对 GPCR 功能影响的数据越来越多,这表明大多数变异似乎由于编码受体蛋白的错误折叠而功能失调,这反过来又导致受体在通过分泌途径转运到细胞表面的过程中受损。因此,这些在细胞内保留的受体可能可以通过使用基于药理学伴侣(PC)的方法进行“挽救”。PC 是一种小分子、细胞可渗透的分子,据推测它可以与错误折叠的在细胞内保留的蛋白质相互作用,稳定其折叠并促进其通过分泌途径转运。作为一种可行的治疗选择,这种方法已经被观察到,许多被“挽救”到细胞表面的挽救变体 GPCR 至少保留了一定程度的功能。在这篇综述中,我们研究了 GPCR PC 研究领域,重点研究了在 HPG 轴中具有重要作用的失活变体 GPCR 的挽救,并描述了已知的 PC 恢复转运和功能的机制。我们还讨论了将这种方法推向临床应用的一些优点和障碍。

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