Visual Arrestin 1 acts as a modulator for N-ethylmaleimide-sensitive factor in the photoreceptor synapse.
In the G-protein-coupled receptor phototransduction cascade, visual Arrestin 1 (Arr1) binds to and deactivates phosphorylated light-activated opsins, a process that is critical for effective recovery and normal vision. In this report, we discovered a novel synaptic interaction between Arr1 and N-ethylmaleimide-sensitive factor (NSF) that is enhanced in a dark environment when mouse photoreceptors are depolarized and the rate of exocytosis is elevated. In the photoreceptor synapse, NSF functions to sustain a higher rate of exocytosis, in addition to the compensatory endocytosis to retrieve and to recycle vesicle membrane and synaptic proteins. Not only does Arr1 bind to the junction of NSF N-terminal and its first ATPase domains in an ATP-dependent manner in vitro, but Arr1 also enhances both NSF ATPase and NSF disassembly activities. In in vivo experiments in mouse retinas with the Arr1 gene knocked out, the expression levels of NSF and other synapse-enriched components, including vGLUT1 (vesicular glutamate transporter 1), EAAT5 (excitatory amino acid transporter 5), and VAMP2 (vesicle-associated membrane protein 2), are markedly reduced, which leads to a substantial decrease in the exocytosis rate with FM1-43. Thus, we propose that the Arr1 and NSF interaction is important for modulating normal synaptic function in mouse photoreceptors. This study demonstrates a vital alternative function for Arr1 in the photoreceptor synapse and provides key insights into the potential molecular mechanisms of inherited retinal diseases, such as Oguchi disease and Arr1-associated retinitis pigmentosa.
Huang
Shun-Ping
SP
Mary D. Allen Laboratory for Vision Research, Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033-9224, USA.
Brown
Bruce M
BM
Craft
Cheryl M
CM
D000704:Analysis of Variance; D000818:Animals; D019393:Arrestin / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D055537:Light Signal Transduction / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D010786:Photoreceptor Cells / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
D019393:Arrestin; D050988:Vesicle-Associated Membrane Protein 2; D052066:N-Ethylmaleimide-Sensitive Proteins