Visual Arrestin 1 Acts As a Modulator for N-Ethylmaleimide-Sensitive Factor in the Photoreceptor Synapse

Abstract

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.

Steric volume exclusion sets soluble protein concentrations in photoreceptor sensory cilia

“…Three binding partners have been identified for arrestin in dark-adapted rods, α-tubulin (24), enolase 1 (26), and NSF (27). However, at ∼50 μm in neural cells (28) and ∼5 μm in rods (26), respectively, α-tubulin and enolase 1 are present in at least two orders of magnitude lower abundance than the greater than millimolar levels of arrestin (8) and NSF is not codistributed with arrestin in dark-or light-adapted rods, being found predominantly within the synaptic spherule (27). Thus, these proteins fail to meet two important criteria required to account for arrestin localization: capacity and codistribution.…”

Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light‐evoked translocation in vivo

“…For example, translocation only occurs if visual cycle regeneration of rhodopsin is normal (6). Another important function of tet-ARR1 is its modulation in the dark of exocytotic activity at the first retinal synapse activity via N-ethylmaleimide sensitive factor (7,8). Defects in ARR1 are implicated in the sight-threatening Oguchi disease, a nonprogressive form of congenital stationary night blindness (9).…”

Arrestin 1 and Cone Arrestin 4 Have Unique Roles in Visual Function in an All-Cone Mouse Retina

“…7 Furthermore, ARR1 is highly expressed in mouse cones and it can substitute for ARR4 in the cone phototransduction shutoff pathway, 7 although transgenic mice with ARR4 expressed in rods lacking ARR1 display deficits in the known functions of ARR1, 16 including phototransduction shutoff, 12 light adaptation, 15 and synaptic function. 17 The concentration of ARR4 in mouse cones is approximately 2% of the total arrestin concentration while the other 98% is arrestin 1, yet at the single-cell level, cone shutoff 7 This indicates that ARR4 has a much higher affinity for cone opsins than ARR1, and has an important role in the termination of the light-activated signal that originates with the cone opsins. Mice lacking both ARR1 and ARR4 display a lack of rod and cone phototransduction shutoff and are unable to light-adapt normally.…”

“…The differences between Nrl À/À , Nrl À/À Arr1 À/À , and Nrl À/À Arr4 À/À mice likely have less to do with phototransduction shutoff, because based on single-cell recordings, phototransduction shutoff occurs normally as long as one visual arrestin is present. 7 We hypothesized that the phenotypes of the Nrl has been shown to interact with and modulate other proteins in mammalian rods, including itself (homo-dimers and tetramers), 1,48-50 microtubules, [51][52][53] Ca 2þ -bound calmodulin, 54 N-ethylmaliemide sensitive factor (NSF), 17 MAP kinases JNK3 55 and ERK2, 53,56,57 E3 ubiquitin ligase Mdm2, 53,55 enolase, 58 Parkin, 59 and Bardet-Biedl syndrome 5 (BBS5).…”

“…62 In addition, ARR1 binds microtubules and potentially keeps ARR1 confined to rod cell bodies and inner segments in the darkadapted state, [50][51][52] and ARR1 modulates synaptic transmission and exocytosis through its interaction with NSF. 17 In many of the studies, the physiological consequences of ARR1 binding and interacting with the other proteins listed above are unclear. A much smaller list of binding partners of ARR4 have been discovered, including JNK3 and MDM2, 55 RND2,63 ALS2CR4/TMEM 237, 64 and DRD4.…”