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

• Published in: Cell reports (Cambridge) 2018-11, Vol.25 (9), p.2497-2509.e4
• Main Authors: Mure, Ludovic S., Hatori, Megumi, Ruda, Kiersten, Benegiamo, Giorgia, Demas, James, Panda, Satchidananda
• Format: Article
• Language: English
• Subjects: Adaptation, Ocular - radiation effects; Amino Acid Sequence; Animals; Animals, Newborn; Behavior, Animal; beta arrestin; beta-Arrestin 1 - metabolism; beta-Arrestin 2 - metabolism; CHO Cells; Cricetinae; Cricetulus; Humans; Light; Light Signal Transduction; melanopsin; Mice; Models, Biological; non-visual responses to light; photophobia; pupillary reflex; Regeneration - radiation effects; retina; retinal ganglion cell; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - radiation effects; Rod Opsins - chemistry; Rod Opsins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.11.008

Melanopsin-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 attenuates 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. [Display omitted] •Phosphorylation of melanopsin upon activation primes binding to β-arrestin 1 and 2•Each β-arrestin regulates different aspects of melanopsin photoresponses•β-Arrestin 2 mediates signal termination, and β-arrestin 1 mediates melanopsin recycling•Both β-arrestins are necessary to sustain melanopsin continuous response The mechanism by which melanopsin-expressing retinal ganglion cells (mRGCs) tonically respond to continuous illumination is unknown. Mure et al. show that phosphorylation-dependent binding of β-arrestin 1 and 2 coordinately deactivate and regenerate melanopsin photopigment to enable sustained firing of mRGCs in response to prolonged illumination.