| First Author | Song X | Year | 2009 |
| Journal | Curr Biol | Volume | 19 |
| Issue | 8 | Pages | 700-5 |
| PubMed ID | 19361994 | Mgi Jnum | J:148930 |
| Mgi Id | MGI:3847155 | Doi | 10.1016/j.cub.2009.02.065 |
| Citation | Song X, et al. (2009) Enhanced arrestin facilitates recovery and protects rods lacking rhodopsin phosphorylation. Curr Biol 19(8):700-5 |
| abstractText | G protein-coupled receptors (GPCRs) are the largest family of signaling proteins expressed in every cell in the body and are targeted by the majority of clinically used drugs [1]. GPCR signaling, including rhodopsin-driven phototransduction, is terminated by receptor phosphorylation followed by arrestin binding [2]. Genetic defects in receptor phosphorylation and excessive signaling by overactive GPCR mutants result in a wide variety of diseases, from retinal degeneration to cancer [3-6]. Here, we tested whether arrestin1 mutants with enhanced ability to bind active unphosphorylated rhodopsin [7-10] can suppress uncontrolled signaling, bypassing receptor phosphorylation by rhodopsin kinase (RK) and replacing this two-step mechanism with a single-step deactivation in rod photoreceptors. We show that in this precisely timed signaling system with single-photon sensitivity [11], an enhanced arrestin1 mutant partially compensates for defects in rhodopsin phosphorylation, promoting photoreceptor survival, improving functional performance, and facilitating photoresponse recovery. These proof-of-principle experiments demonstrate the feasibility of functional compensation in vivo for the first time, which is a promising approach for correcting genetic defects associated with gain-of-function mutations. Successful modification of protein-protein interactions by appropriate mutations paves the way to targeted redesign of signaling pathways to achieve desired functional outcomes. |
