Gimenez Luis E, Vishnivetskiy Sergey A, Gurevich Vsevolod V
Department of Pharmacology, Vanderbilt University, 2200 Pierce Avenue, Nashville, TN, 37232, USA,
Handb Exp Pharmacol. 2014;219:153-70. doi: 10.1007/978-3-642-41199-1_8.
Numerous human diseases are caused by excessive signaling of mutant G protein-coupled receptors (GPCRs) or receptors that are overstimulated due to upstream signaling imbalances. The feasibility of functional compensation by arrestins with enhanced ability to quench receptor signaling was recently tested in the visual system. The results showed that even in this extremely demanding situation of rods that have no ability to phosphorylate rhodopsin, enhanced arrestin improved rod morphology, light sensitivity, survival, and accelerated photoresponse recovery. Structurally distinct enhanced mutants of arrestins that bind phosphorylated and non-phosphorylated active GPCRs with much higher affinity than parental wild-type (WT) proteins have been constructed. These "super-arrestins" are likely to have the power to dampen the signaling by hyperactive GPCRs. However, most cells express 5-20 GPCR subtypes, only one of which would be overactive, while nonvisual arrestins are remarkably promiscuous, binding hundreds of different GPCRs. Thus, to be therapeutically useful, enhanced versions of nonvisual arrestins must be made fairly specific for particular receptors. Recent identification of very few arrestin residues as key receptor discriminators paves the way to the construction of receptor subtype-specific nonvisual arrestins.
许多人类疾病是由突变的G蛋白偶联受体（GPCR）过度信号传导或由于上游信号失衡而过度刺激的受体引起的。最近在视觉系统中测试了具有增强的淬灭受体信号传导能力的抑制蛋白进行功能补偿的可行性。结果表明，即使在视杆细胞这种无法磷酸化视紫红质的极端苛刻情况下，增强的抑制蛋白也能改善视杆细胞形态、光敏感性、存活率，并加速光反应恢复。已经构建了结构上不同的抑制蛋白增强突变体，它们与磷酸化和非磷酸化的活性GPCR结合的亲和力比亲本野生型（WT）蛋白高得多。这些“超级抑制蛋白”可能有能力抑制过度活跃的GPCR的信号传导。然而，大多数细胞表达5-20种GPCR亚型，其中只有一种会过度活跃，而非视觉抑制蛋白非常混杂，能结合数百种不同的GPCR。因此，为了具有治疗用途，非视觉抑制蛋白的增强版本必须对特定受体具有相当的特异性。最近鉴定出极少数抑制蛋白残基作为关键的受体鉴别位点，为构建受体亚型特异性的非视觉抑制蛋白铺平了道路。
