Protein Phosphatase 2A and Clathrin-Mediated Endocytosis Facilitate Robust Melanopsin Light Responses and Resensitization

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dc.contributor.authorValdez-Lopez, Juan C.
dc.contributor.authorGebreegziabher, Meheret
dc.contributor.authorBailey, Robin J.
dc.contributor.authorFlores, Jair
dc.contributor.authorAwotunde, Olanike
dc.contributor.authorBurnett, Thomas
dc.contributor.authorRobinson, Phyllis R.
dc.date.accessioned2020-11-19T16:33:34Z
dc.date.available2020-11-19T16:33:34Z
dc.date.issued2020-10
dc.description.abstractPurpose: Intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the visual pigment melanopsin regulate non-image-forming visual tasks, such as circadian photoentrainment and pupil constriction, as well as contrast detection for image formation. Sustained ipRGC function throughout the day is, therefore, of great importance. Melanopsin is a bistable rhabdomeric-type (R-type) visual pigment, which is thought to use light to regenerate its chromophore from all-trans-retinal back to 11-cis-retinal and does not depend on constant chromophore supply to the extent required by visual pigment in rod and cone photoreceptors. Like the majority of photopigments and G-protein-coupled receptors (GPCRs), melanopsin deactivation requires C-terminal phosphorylation and subsequent β-arrestin binding. We hypothesize that melanopsin utilizes canonical GPCR resensitization mechanisms, including dephosphorylation and endocytosis, during the light, and together, they provide a mechanism for prolonged light responses. Methods: Here, we examined expression of protein phosphatases from a variety of subfamilies by RT-PCR and immunohistochemical analyses of the mouse retina. The expression of protein phosphatase 2A (PP2A) in ipRGCs was assessed. We also examine the role of phosphatase and endocytic activity in sustaining melanopsin signaling using transiently-transfected HEK293 cells. Results: Our analyses suggest that melanopsin-mediated light responses can be rapidly and extensively enhanced by PP2A activity. Light-activated melanopsin undergoes endocytosis in a clathrin-dependent manner. This endocytic activity enhances light responses upon repeated stimulation, implicating a role for endocytic activity in resensitization. Conclusions: Thus, we propose that melanopsin phototransduction is maintained by utilizing canonical GPCR resensitization mechanisms rather than reliance on chromophore replenishment from supporting cells.en_US
dc.description.sponsorshipThe authors thank Daniel Oprian, PhD, for generously supplying them with 1D4 antibody and Nansi J. Colley, PhD, and R. Lane Brown, PhD, for reading and commenting on the manuscript. JCV-L also thanks and acknowledges Adam Byerly for assistance with calcium imaging assays. Supported by NIH Training Grant T32 GM066706 awarded to JCV-L, generously made possible by Katherine Seley-Radtke, PhD; NIH R01 EY027202-01A1, awarded to PRR; and T34GM008663 award, given to TB and RJB.en_US
dc.description.urihttps://iovs.arvojournals.org/article.aspx?articleid=2770904en_US
dc.format.extent12 pagesen_US
dc.genrejournal articlesen_US
dc.identifierdoi:10.13016/m24rmn-kxig
dc.identifier.citationValdez-Lopez JC, Gebreegziabher M, Bailey RJ, et al. Protein phosphatase 2A and clathrin-mediated endocytosis facilitate robust melanopsin light responses and resensitization. Invest Ophthalmol Vis Sci. 2020;61(12):10. https://doi.org/10.1167/iovs.61.12.10en_US
dc.identifier.urihttps://doi.org/10.1167/iovs.61.12.10
dc.identifier.urihttp://hdl.handle.net/11603/20091
dc.language.isoen_USen_US
dc.publisherARVOen_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Biological Sciences Department Collection
dc.relation.ispartofUMBC Faculty Collection
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titleProtein Phosphatase 2A and Clathrin-Mediated Endocytosis Facilitate Robust Melanopsin Light Responses and Resensitizationen_US
dc.typeTexten_US
dcterms.rightsAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

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