The endocytic pathway tightly controls the activity of G protein-coupled receptors (GPCRs). Ligand-induced endocytosis can drive receptors into divergent lysosomal and recycling pathways, producing essentially opposite effects on the strength and duration of cellular signaling via heterotrimeric G proteins, and may also promote distinct signaling events from intracellular membranes. This chapter reviews recent developments toward understanding the molecular machinery and functional implications of GPCR sorting in the endocytic pathway, focusing on mammalian GPCRs whose ligand-induced endocytosis is mediated primarily by clathrin-coated pits. Lysosomal sorting of a number of GPCRs occurs via a highly conserved mechanism requiring covalent tagging of receptors with ubiquitin. There is increasing evidence that additional, noncovalent mechanisms control the sorting of endocytosed GPCRs to lysosomes in mammalian cells. Recycling of several GPCRs to the plasma membrane is also specifically sorted, via a mechanism requiring both receptor-specific and shared sorting proteins. The current data reveal an unprecedented degree of specificity and plasticity in the cellular regulation of mammalian GPCRs by endocytic membrane trafficking. These developments have fundamental implications for GPCR pharmacology, and suggest new mechanisms that could be exploited in GPCR-directed pharmacotherapy.

中文翻译：

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内吞膜运输对GPCR的调控及其潜在意义。

内吞途径严格控制G蛋白偶联受体（GPCR）的活性。配体诱导的内吞作用可以驱使受体进入不同的溶酶体和再循环途径，通过异源三聚体G蛋白对细胞信号传导的强度和持续时间产生基本相反的作用，并且还可能促进来自细胞内膜的独特信号传导事件。本章回顾了了解内吞途径中GPCR排序的分子机制和功能含义的最新进展，重点是哺乳动物GPCR，其配体诱导的内吞作用主要由网格蛋白包被的凹坑介导。许多GPCR的溶酶体分选是通过高度保守的机制发生的，该机制要求用泛素共价标记受体。越来越多的证据表明，非共价机制控制内吞GPCR对哺乳动物细胞中溶酶体的分类。还通过一种既需要受体特异性蛋白又需要共享蛋白的机制对几种GPCR再循环到质膜上进行了专门分类。当前数据揭示了通过内吞膜运输对哺乳动物GPCR的细胞调节的特异性和可塑性的空前程度。这些进展对GPCR药理学具有根本意义，并暗示了可在GPCR指导的药物治疗中开发的新机制。当前数据揭示了通过内吞膜运输对哺乳动物GPCR的细胞调节的特异性和可塑性的空前程度。这些进展对GPCR药理学具有根本意义，并暗示了可在GPCR指导的药物治疗中开发的新机制。当前数据揭示了通过内吞膜运输对哺乳动物GPCR的细胞调节的特异性和可塑性的空前程度。这些进展对GPCR药理学具有根本意义，并暗示了可在GPCR指导的药物治疗中开发的新机制。