Enhanced Arrestin Facilitates Recovery and Protects Rods Lacking Rhodopsin Phosphorylation

Xiufeng Song, Sergey A. Vishnivetskiy, Owen P. Gross, Katrina Emelianoff, Ana Mendez, Jeannie Chen, Eugenia V. Gurevich, Marie E Burns, Vsevolod V. Gurevich

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)700-705
Number of pages6
JournalCurrent Biology
Volume19
Issue number8
DOIs
StatePublished - Apr 28 2009

Keywords

  • CELLBIO
  • SIGNALING

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Song, X., Vishnivetskiy, S. A., Gross, O. P., Emelianoff, K., Mendez, A., Chen, J., Gurevich, E. V., Burns, M. E., & Gurevich, V. V. (2009). Enhanced Arrestin Facilitates Recovery and Protects Rods Lacking Rhodopsin Phosphorylation. Current Biology, 19(8), 700-705. https://doi.org/10.1016/j.cub.2009.02.065