Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Pharmacol Rev. 2011 Dec;63(4):882-900. doi: 10.1124/pr.110.004176. Epub 2011 Aug 26.
Many G protein-coupled receptors (GPCR) exert patterns of cell-specific signaling and function. Mounting evidence now supports the view that cytoplasmic adapter proteins contribute critically to this behavior. Adapter proteins recognize highly conserved motifs such as those for Src homology 3 (SH3), phosphotyrosine-binding (PTB), and postsynaptic density 95/discs-large/zona occludens (PDZ) docking sequences in candidate GPCRs. Here we review the behavior of the Na+/H+ exchange regulatory factor (NHERF) family of PDZ adapter proteins on GPCR signalling, trafficking, and function. Structural determinants of NHERF proteins that allow them to recognize targeted GPCRs are considered. NHERF1 and NHERF2 are capable also of modifying the assembled complex of accessory proteins such as β-arrestins, which have been implicated in regulating GPCR signaling. In addition, NHERF1 and NHERF2 modulate GPCR signaling by altering the G protein to which the receptor binds or affect other regulatory proteins that affect GTPase activity, protein kinase A, phospholipase C, or modify downstream signaling events. Small molecules targeting the site of NHERF1-GPCR interaction are being developed and may become important and selective drug candidates.
许多 G 蛋白偶联受体 (GPCR) 表现出细胞特异性信号传递和功能的模式。越来越多的证据支持这样一种观点，即细胞质衔接蛋白对这种行为起着至关重要的作用。衔接蛋白识别高度保守的基序，如Src 同源 3 (SH3)、磷酸酪氨酸结合 (PTB) 和突触后密度 95/离散大/区室封闭 (PDZ) 对接序列在候选 GPCR 中。在这里，我们回顾了 PDZ 衔接蛋白家族的 Na+/H+交换调节因子 (NHERF) 对 GPCR 信号转导、运输和功能的作用。考虑了 NHERF 蛋白识别靶向 GPCR 的结构决定因素。NHERF1 和 NHERF2 还能够修饰β-arrestin 等辅助蛋白的组装复合物，β-arrestin 已被牵连到调节 GPCR 信号转导。此外，NHERF1 和 NHERF2 通过改变受体结合的 G 蛋白或影响其他调节蛋白来改变 GTP 酶活性、蛋白激酶 A、磷脂酶 C 或修饰下游信号事件，从而调节 GPCR 信号转导。针对 NHERF1-GPCR 相互作用位点的小分子正在被开发，并可能成为重要的和选择性的药物候选物。
