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.
Song
Xiufeng
X
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Vishnivetskiy
Sergey A
SA
Gross
Owen P
OP
Emelianoff
Katrina
K
Mendez
Ana
A
Chen
Jeannie
J
Gurevich
Eugenia V
EV
Burns
Marie E
ME
Gurevich
Vsevolod V
VV
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