G protein-coupled receptors (GPCRs) recognize a diverse array of extracellular stimuli, and they mediate a broad repertoire of signaling events involved in human physiology. Although the major effort on targeting GPCRs has typically been focused on their extracellular surface, a series of recent developments now unfold the possibility of targeting them from the intracellular side as well. Allosteric modulators binding to the cytoplasmic surface of GPCRs have now been described, and their structural mechanisms are elucidated by high-resolution crystal structures. Furthermore, pepducins, aptamers, and intrabodies targeting the intracellular face of GPCRs have also been successfully utilized to modulate receptor signaling. Moreover, small molecule compounds, aptamers, and synthetic intrabodies targeting β-arrestins have also been discovered to modulate GPCR endocytosis and signaling. Here, we discuss the emerging paradigm of intracellular targeting of GPCRs, and outline the current challenges, potential opportunities, and future outlook in this particular area of GPCR biology.

G蛋白偶联受体（GPCR）识别各种各样的细胞外刺激，它们介导了涉及人类生理学的多种信号转导事件。尽管针对GPCR的主要努力通常集中在其细胞外表面，但一系列最新进展现在也揭示了从细胞内侧靶向GPCR的可能性。现在已经描述了与GPCR胞质表面结合的变构调节剂，并通过高分辨率晶体结构阐明了它们的结构机理。此外，靶向GPCR的细胞内表面的pepducins，适体和体内抗体也已经成功地用于调节受体信号传导。此外，小分子化合物，适体，还发现靶向β-arrestin的合成体内抗体可调节GPCR的内吞作用和信号传导。在这里，我们讨论了GPCR的细胞内靶向的新兴范例，并概述了GPCR生物学这一特定领域中的当前挑战，潜在机遇和未来前景。