Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors

Alexander V. Kolesnikov; Tivadar Orban; Hui Jin; Celine Brooks; Lukas Hofmann; Zhiqian Dong; Maxim Sokolov; Krzysztof Palczewski; Vladimir J. Kefalov

doi:10.1073/pnas.1712405114

Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors

Alexander V. Kolesnikov, Tivadar Orban, Hui Jin, Celine Brooks, Lukas Hofmann, Zhiqian Dong, Maxim Sokolov, Krzysztof Palczewski, Vladimir J. Kefalov

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Resetting of G-protein–coupled receptors (GPCRs) from their active state back to their biologically inert ground state is an integral part of GPCR signaling. This “on–off” GPCR cycle is regulated by reversible phosphorylation. Retinal rod and cone photoreceptors arguably represent the best-understood example of such GPCR signaling. Their visual pigments (opsins) are activated by light, transduce the signal, and are then inactivated by a GPCR kinase and arrestin. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain unknown. Here, we show that protein phosphatase 2A (PP2A) acts as opsin phosphatase in both rods and cones. Elimination of PP2A substantially slows pigment dephosphorylation, visual chromophore recycling, and ultimately photoreceptor dark adaptation. These findings demonstrate that visual pigment dephosphorylation regulates the dark adaptation of photoreceptors and provide insights into the role of this reaction in GPCR signaling.

Original language	English
Pages (from-to)	E9675-E9684
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	45
DOIs	https://doi.org/10.1073/pnas.1712405114
State	Published - 7 Nov 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.

Funding

ACKNOWLEDGMENTS. We are thankful to the V.J.K. and K.P. laboratories for comments on the manuscript. Especially, we thank Drs. Ning Zhang and Jianye Zhang for their help during this study. This work was supported by NIH Grants EY026675 (to V.J.K. and K.P.), EY019312 (to V.J.K.), and EY02687 (Department of Ophthalmology and Visual Sciences, Washington University), and by Research to Prevent Blindness. L.H. is supported by a Swiss National Science Foundation Doc.Mobility Fellowship (P1SKP3_158634). K.P. is John H. Hord Professor of Pharmacology.

Funders	Funder number
National Institutes of Health	EY019312, EY026675
National Eye Institute	P30EY002687
Research to Prevent Blindness
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	P1SKP3_158634

Keywords

Dark adaptation
GPCRs
PP2A
Photoreceptors
Visual cycle

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10.1073/pnas.1712405114

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Kolesnikov, A. V., Orban, T., Jin, H., Brooks, C., Hofmann, L., Dong, Z., Sokolov, M., Palczewski, K., & Kefalov, V. J. (2017). Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors. Proceedings of the National Academy of Sciences of the United States of America, 114(45), E9675-E9684. https://doi.org/10.1073/pnas.1712405114

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abstract = "Resetting of G-protein–coupled receptors (GPCRs) from their active state back to their biologically inert ground state is an integral part of GPCR signaling. This “on–off” GPCR cycle is regulated by reversible phosphorylation. Retinal rod and cone photoreceptors arguably represent the best-understood example of such GPCR signaling. Their visual pigments (opsins) are activated by light, transduce the signal, and are then inactivated by a GPCR kinase and arrestin. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain unknown. Here, we show that protein phosphatase 2A (PP2A) acts as opsin phosphatase in both rods and cones. Elimination of PP2A substantially slows pigment dephosphorylation, visual chromophore recycling, and ultimately photoreceptor dark adaptation. These findings demonstrate that visual pigment dephosphorylation regulates the dark adaptation of photoreceptors and provide insights into the role of this reaction in GPCR signaling.",

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Kolesnikov, AV, Orban, T, Jin, H, Brooks, C, Hofmann, L, Dong, Z, Sokolov, M, Palczewski, K & Kefalov, VJ 2017, 'Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 45, pp. E9675-E9684. https://doi.org/10.1073/pnas.1712405114

Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors. / Kolesnikov, Alexander V.; Orban, Tivadar; Jin, Hui et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 45, 07.11.2017, p. E9675-E9684.

Research output: Contribution to journal › Article › peer-review

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Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors

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