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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引用次数: 0

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.

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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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