Maya-Núñez Guadalupe, Ulloa-Aguirre Alfredo, Janovick Jo Ann, Conn P Michael
Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR, 97006, USA,
Subcell Biochem. 2012;63:263-89. doi: 10.1007/978-94-007-4765-4_14.
G-protein-coupled receptors (GPCRs) are a large superfamily of plasma membrane proteins that play central roles in transducing endocrine, neural and -sensory signals. In humans, more than 30 disorders are associated with mutations in GPCRs and these proteins are common drug development targets, with 30-50% of drugs targeting them. GPCR mutants are frequently misfolded, recognized as defective by the cellular quality control system, retained in the endoplasmic reticulum and do not traffic to the plasma membrane. The use of small molecules chaperones (pharmacological chaperones or "pharmacoperones") to rescue misfolded GPCRs has provided a new approach for treatment of human diseases caused by misfolding and misrouting. This chapter provides an overview of the molecular basis of this approach using the human gonadotropin-releasing hormone receptor (hGnRHR) as model for treatment of conformational diseases provoked by -misfolded GPCRs.
G蛋白偶联受体（GPCRs）是一大类质膜蛋白超家族，在转导内分泌、神经和感觉信号中起核心作用。在人类中，超过30种疾病与GPCRs的突变有关，这些蛋白是常见的药物开发靶点，30%-50%的药物以它们为靶点。GPCR突变体经常错误折叠，被细胞质量控制系统识别为有缺陷，滞留在内质网中，无法转运到质膜。使用小分子伴侣（药理伴侣或“药效伴侣”）来挽救错误折叠的GPCRs为治疗由错误折叠和错误转运引起的人类疾病提供了一种新方法。本章以人促性腺激素释放激素受体（hGnRHR）为例，概述了这种方法的分子基础，用于治疗由错误折叠的GPCRs引发的构象疾病。
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