Sustained Melanopsin Photoresponse Is Supported by Specific Roles of β-Arrestin 1 and 2 in Deactivation and Regeneration of Photopigment

Ludovic S Mure,Megumi Hatori,Kiersten Ruda,Giorgia Benegiamo,James Demas,Satchidananda Panda

doi:10.1016/j.celrep.2018.11.008

Ludovic S Mure, Megumi Hatori + Show 4 more

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https://doi.org/10.1016/j.celrep.2018.11.008

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Abstract

SUMMARYMelanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are indispensable for non-image-forming visual responses that sustain under prolonged illumination. For sustained signaling of ipRGCs, the melanopsin photopigment must continuously regenerate. The underlying mechanism is unknown. We discovered that a cluster of Ser/Thr sites within the C-terminal region of mammalian melanopsin is phosphorylated after a light pulse. This forms a binding site for β-arrestin 1 (βARR1) and β-arrestin 2. β-arrestin 2 primarily regulates the deactivation of melanopsin; accordingly, βαrr2–/–mice exhibit prolonged ipRGC responses after cessation of a light pulse. β-arrestin 1 primes melanopsin for regeneration. Therefore, βαrr1–/– ipRGCs become desensitized after repeated or prolonged photostimulation. The lack of either β-arrestin atten-uates ipRGC response under prolonged illumination, suggesting that β-arrestin 2-mediated deactivation and β-arrestin 1-dependent regeneration of melanopsin function in sequence. In conclusion, we discovered a molecular mechanism by which β-arrestins regulate different aspects of melanopsin photoresponses and allow ipRGC-sustained responses under prolonged illumination.

Highlights

Melanopsin is an opsin class of photopigment that is expressed in a subset of retinal ganglion cells (RGCs), rendering them intrinsically photosensitive
By using viral vectors to express melanopsin in random RGCs or in intrinsically photosensitive retinal ganglion cells (ipRGCs), we discovered that ipRGCs have an inherent ability to sustain light responses when exposed to repeated long pulses of light, whereas photoresponses of other RGCs reduce in magnitude or adapt to repeated photostimulation. b-arrestin 1 and b-arrestin 2 both interact with melanopsin, and their binding affinity increases upon light-dependent phosphorylation of melanopsin
Sorted into 2 clusters, cells from each genotype revealed response profiles and distributions (Figure S3B) similar to types II and III ipRGCs, as reported by Tu et al (2005). Both subtypes displayed the same longer responses in rd;barr2À/À mice compared to the equivalent groups in rd mice (Figure S3C). These results indicated that alterations observed in rd;barr1À/À or rd;barr2À/À mice reflect the roles of specific b-arrestins in melanopsin function

Summary

Introduction

Melanopsin is an opsin class of photopigment that is expressed in a subset of retinal ganglion cells (RGCs), rendering them intrinsically photosensitive (ipRGCs). Melanopsin plays a pivotal role in non-image-forming (NIF) responses to light, including physiological adaptations (of pupil size, circadian rhythm, and activity) to ambient light (Nayak et al, 2007). Many of the NIF visual responses mediated by melanopsin are sustained under continuous illumination, and such sustained responses are necessary for behavioral adaptation to ambient light. The sustained response of melanopsin is necessary for light-induced activity suppression (negative masking) and photophobia in rodents. The lack of melanopsin, even in the presence of intact rod and cone function, attenuates masking under prolonged illumination (Johnson et al, 2010; Mrosovsky and Hattar, 2003). The mechanism or mechanisms underlying melanopsin function under continuous illumination are largely unknown

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