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

Cell Rep. 2018 Nov 27;25(9):2497-2509.e4. 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.

Keywords: beta arrestin; melanopsin; non-visual responses to light; photophobia; pupillary reflex; retina; retinal ganglion cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Ocular / radiation effects
  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Behavior, Animal
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • Light Signal Transduction
  • Light*
  • Mice
  • Models, Biological
  • Regeneration / radiation effects*
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / radiation effects
  • Rod Opsins / chemistry
  • Rod Opsins / metabolism*
  • beta-Arrestin 1 / metabolism*
  • beta-Arrestin 2 / metabolism*


  • Rod Opsins
  • beta-Arrestin 1
  • beta-Arrestin 2
  • melanopsin