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

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 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.