Enhanced arrestin facilitates recovery and protects rods lacking rhodopsin phosphorylation.
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.
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Xiufeng
X
Song
Sergey A
SA
Vishnivetskiy
Owen P
OP
Gross
Katrina
K
Emelianoff
Ana
A
Mendez
Jeannie
J
Chen
Eugenia V
EV
Gurevich
Marie E
ME
Burns
Vsevolod V
VV
Gurevich
D000818:Animals; D019393:Arrestin / Q000235:genetics / Q000378:metabolism*; D004596:Electroretinography; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism*
D019393:Arrestin; D012243:Rhodopsin; D051606:G-Protein-Coupled Receptor Kinase 1