Targeting individual GPCRs with redesigned nonvisual arrestins.

Gimenez LE, Vishnivetskiy SA, Gurevich VV
Handb Exp Pharmacol. 2014 219: 153-70

PMID: 24292829 · PMCID: PMC4516156 · 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.

MeSH Terms (10)

Animals Arrestins Humans Mutation Phosphates Phosphorylation Receptors, G-Protein-Coupled Retinal Rod Photoreceptor Cells Rhodopsin Signal Transduction

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