Folding, misfolding, and regulation of intracellular traffic of G protein-coupled receptors involved in the hypothalamic-pituitary-gonadal axis.

IF 3.2 2区 医学 Q1 ANDROLOGY
Andrology Pub Date : 2025-03-07 DOI:10.1111/andr.70018
Alfredo Ulloa-Aguirre, Ross C Anderson, Teresa Zariñán, Rubén Gutiérrez-Sagal, Eduardo Jardón-Valadez, Claire L Newton
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Abstract

Background: G protein-coupled receptors are a large and functionally diverse family of membrane receptors involved in a number of biological processes. Like other proteins, G protein-coupled receptors need to be properly folded in order to traffic to the plasma membrane and interact with agonist.

Objective: Herein, we briefly review the process of folding and intracellular traffic of G protein-coupled receptors, with a focus on the gonadotropin-releasing hormone receptor and the gonadotropin receptors, whose variants can lead to misfolding, loss of plasma membrane trafficking and eventually to different forms of hypogonadism.

Results and discussion: Pathogenic variants of G protein-coupled receptors may provoke loss-of-function of the receptor protein, thereby leading to disease. The presence of a stringent cellular quality control system promotes proper protein folding compatible with endoplasmic reticulum export and concomitantly prevents unfolded proteins accumulating within the cell. Molecular chaperones and companion factors are key elements of the quality control system that maintain the integrity of the proteostasis network by regulating, at different levels folding and assembly of nascent proteins and by promoting degradation of defective conformers, preventing aggregation and toxic accumulation. Due to the importance of the concept of molecular chaperoning in protein folding, pharmacoperone drugs emulating the role of endogenous chaperones as stabilizers of protein conformation currently represent a novel therapeutic opportunity for rescuing misfolded receptors and treating different diseases due to protein misfolding.

Conclusions: In vitro and in vivo studies in experimental animals and in humans have provided proof-of-principle of the beneficial effects of pharmacoperone drugs in modifying the course of human disease due to misfolding of G protein-coupled receptors.

参与下丘脑-垂体-性腺轴的G蛋白偶联受体的折叠、错误折叠和细胞内交通调节。
背景:G蛋白偶联受体是一个庞大且功能多样的膜受体家族,参与许多生物过程。与其他蛋白质一样,G蛋白偶联受体需要适当折叠才能运输到质膜并与激动剂相互作用。目的:本文简要综述了G蛋白偶联受体的折叠和细胞内转运过程,重点介绍了促性腺激素释放激素受体和促性腺激素受体,它们的变异可导致错误折叠,失去质膜转运,最终导致不同形式的性腺功能低下。结果与讨论:G蛋白偶联受体的致病性变异可能引起受体蛋白功能丧失,从而导致疾病。严格的细胞质量控制系统的存在促进了与内质网输出兼容的适当蛋白质折叠,同时防止未折叠蛋白质在细胞内积累。分子伴侣和伴侣因子是质量控制系统的关键要素,通过在不同水平上调节新生蛋白质的折叠和组装,促进有缺陷的构象的降解,防止聚集和毒性积累,维持蛋白质静止网络的完整性。由于分子伴侣在蛋白质折叠中的重要性,模拟内源性伴侣作为蛋白质构象稳定剂的药物,目前为挽救错误折叠的受体和治疗蛋白质错误折叠引起的不同疾病提供了新的治疗机会。结论:实验动物和人体的体外和体内研究已经提供了药物酮药物在改变由于G蛋白偶联受体错误折叠引起的人类疾病过程中的有益作用的原理证明。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Andrology
Andrology ANDROLOGY-
CiteScore
9.10
自引率
6.70%
发文量
200
期刊介绍: Andrology is the study of the male reproductive system and other male gender related health issues. Andrology deals with basic and clinical aspects of the male reproductive system (gonads, endocrine and accessory organs) in all species, including the diagnosis and treatment of medical problems associated with sexual development, infertility, sexual dysfunction, sex hormone action and other urological problems. In medicine, Andrology as a specialty is a recent development, as it had previously been considered a subspecialty of urology or endocrinology
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