G protein-coupled receptors (GPCRs) transduce a wide array of extracellular signals and regulate virtually every aspect of physiology. While GPCR signaling is essential, overstimulation can be deleterious, resulting in cellular toxicity or uncontrolled cellular growth. Accordingly, nature has developed a number of mechanisms for limiting GPCR signaling, which are broadly referred to as desensitization, and refer to a decrease in response to repeated or continuous stimulation. Short-term desensitization occurs over minutes, and is primarily associated with β-arrestins preventing G protein interaction with a GPCR. Longer-term desensitization, referred to as downregulation, occurs over hours to days, and involves receptor internalization into vesicles, degradation in lysosomes and decreased receptor mRNA levels through unclear mechanisms. Phosphorylation of the receptor by GPCR kinases (GRKs) and the recruitment of β-arrestins is critical to both these short- and long-term desensitization mechanisms. In addition to phosphorylation, both the GPCR and β-arrestins are modified post-translationally in several ways, including by ubiquitination. For many GPCRs, receptor ubiquitination promotes degradation of agonist-activated receptors in the lysosomes. Other proteins also play important roles in desensitization, including phosphodiesterases, RGS family proteins and A-kinase-anchoring proteins. Together, this intricate network of kinases, ubiquitin ligases, and adaptor proteins orchestrate the acute and prolonged desensitization of GPCRs.

G蛋白偶联受体（GPCR）会转导大量细胞外信号，并实际上调节生理的各个方面。尽管GPCR信号转导至关重要，但过度刺激可能有害，导致细胞毒性或细胞生长不受控制。因此，自然界已经开发出多种用于限制GPCR信号转导的机制，广泛地被称为脱敏，并且是指对重复或连续刺激的响应降低。短期脱敏发生在几分钟内，并且主要与β-arrestin相关联，从而阻止G蛋白与GPCR相互作用。长期的脱敏被称为下调，持续数小时至数天，涉及受体内化到囊泡中，溶酶体降解以及受体mRNA水平降低（通过不清楚的机制）。GPCR激酶（GRKs）受体的磷酸化和β-arrestin的募集对于这些短期和长期的脱敏机制均至关重要。除磷酸化外，GPCR和β-arrestin均可通过多种方式进行翻译后修饰，包括泛素化。对于许多GPCR，受体泛素化促进了溶酶体中激动剂激活受体的降解。其他蛋白质在脱敏中也起着重要作用，包括磷酸二酯酶，RGS家族蛋白质和A激酶锚定蛋白质。复杂的激酶，泛素连接酶和衔接子蛋白的复杂网络共同构成了GPCR的急性和长期脱敏。除磷酸化外，GPCR和β-arrestin均可通过多种方式进行翻译后修饰，包括泛素化。对于许多GPCR，受体泛素化促进了溶酶体中激动剂激活的受体的降解。其他蛋白质在脱敏中也起着重要作用，包括磷酸二酯酶，RGS家族蛋白质和A激酶锚定蛋白质。复杂的激酶，泛素连接酶和衔接子蛋白的复杂网络共同构成了GPCR的急性和长期脱敏。除磷酸化外，GPCR和β-arrestin均可通过多种方式进行翻译后修饰，包括泛素化。对于许多GPCR，受体泛素化促进了溶酶体中激动剂激活受体的降解。其他蛋白质在脱敏中也起着重要作用，包括磷酸二酯酶，RGS家族蛋白质和A激酶锚定蛋白质。复杂的激酶，泛素连接酶和衔接子蛋白的复杂网络共同构成了GPCR的急性和长期脱敏。包括磷酸二酯酶，RGS家族蛋白和A激酶锚定蛋白。复杂的激酶，泛素连接酶和衔接子蛋白的复杂网络共同构成了GPCR的急性和长期脱敏。包括磷酸二酯酶，RGS家族蛋白和A激酶锚定蛋白。复杂的激酶，泛素连接酶和衔接子蛋白的复杂网络共同构成了GPCR的急性和长期脱敏。