title: C-terminal phosphorylation regulates the kinetics of a subset of melanopsin-mediated behaviors in mice.
abstract: Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and mediate several non-image-forming visual functions, including circadian photoentrainment and the pupillary light reflex (PLR). ipRGCs act as autonomous photoreceptors via the intrinsic melanopsin-based phototransduction pathway and as a relay for rod/cone input via synaptically driven responses. Under low light intensities, where only synaptically driven rod/cone input activates ipRGCs, the duration of the ipRGC response will be determined by the termination kinetics of the rod/cone circuits. Little is known, however, about the termination kinetics of the intrinsic melanopsin-based phototransduction pathway and its contribution to several melanopsin-mediated behaviors. Here, we show that C-terminal phosphorylation of melanopsin determines the recovery kinetics of the intrinsic melanopsin-based photoresponse in ipRGCs, the duration of the PLR, and the speed of reentrainment. In contrast, circadian phase alignment and direct effects of light on activity (masking) are not influenced by C-terminal phosphorylation of melanopsin. Electrophysiological measurements demonstrate that expression of a virally encoded melanopsin lacking all C-terminal phosphorylation sites (C terminus phosphonull) leads to a prolonged intrinsic light response. In addition, mice expressing the C terminus phosphonull in ipRGCs reentrain faster to a delayed light/dark cycle compared with mice expressing virally encoded WT melanopsin; however, the phase angle of entrainment and masking were indistinguishable. Importantly, a sustained PLR in the phosphonull animals is only observed at brighter light intensities that activate melanopsin phototransduction, but not at dimmer light intensities that activate only the rod/cone pathway. Taken together, our results highlight how the kinetics of the melanopsin photoresponse differentially regulate distinct light-mediated behaviors.
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250.
authors.forename: Preethi
authors.initials: P
authors.lastname: Somasundaram
authors.affiliation: Department of Integrative Physiology & Neuroscience, Washington State University, Pullman, WA 99164.
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Wyrick
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: Diego Carlos
authors.initials: DC
authors.lastname: Fernandez
authors.affiliation: Retinal Circuit Development & Genetics Unit, Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Alireza
authors.initials: A
authors.lastname: Ghahari
authors.affiliation: Department of Integrative Physiology & Neuroscience, Washington State University, Pullman, WA 99164.
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Pinhal
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: Melissa
authors.initials: M
authors.lastname: Simmonds Richardson
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Rupp
authors.affiliation: Genetic Epidemiology Research Branch, National Institute of Mental Health, Bethesda, MD 20892.
authors.forename: Lihong
authors.initials: L
authors.lastname: Cui
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Integrative Physiology & Neuroscience, Washington State University, Pullman, WA 99164.
authors.forename: R Lane
authors.initials: RL
authors.lastname: Brown
authors.affiliation: Retinal Circuit Development & Genetics Unit, Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Tudor Constantin
authors.initials: TC
authors.lastname: Badea
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218; shattar@jhu.edu probinso@umbc.edu.|Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21218.
authors.forename: Samer
authors.identifier: 0000-0002-3124-9525
authors.initials: S
authors.lastname: Hattar
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250; shattar@jhu.edu probinso@umbc.edu.
authors.forename: Phyllis R
authors.initials: PR
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002940:Circadian Rhythm / Q000235:genetics; D007700:Kinetics; D008027:Light; D055537:Light Signal Transduction / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000502:physiology; D012025:Reflex, Pupillary / Q000235:genetics / Q000502:physiology; D012160:Retina / Q000378:metabolism / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000502:physiology; D017299:Rod Opsins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D014785:Vision, Ocular / Q000235:genetics / Q000502:physiology; D000099210:Melanopsin
chemical_list: D017299:Rod Opsins; D000099210:Melanopsin
keywords: ipRGCs; phosphorylation; photoentrainment; photoreceptors; phototransduction