The melanopsin expressing intrinsically photosensitive retinal ganglion cells (mRGCs or ipRGCs) are necessary for adapting non-image forming behavior and physiology of the animal to the ambient light conditions. Melanopsin photopigment uses a signaling mechanism that is distinct from that of the classical rod/cone opsins. Very little is known about the molecular events following melanopsin activation. Specifically, molecules and mechanisms mediating photopigment desensitization, internalization, degradation or regeneration of functional photopigment are unknown. These steps in receptor function determine the threshold sensitivity, adaptation and temporal integration parameters. We have determined the C-terminus cytoplasmic region of melanopsin is phosphorylated at multiple sites and is required for its functional interaction with arrestin and subsequent desensitization. Experiments proposed in this application will evaluate the relevance of melanopsin phosphorylation and arrestin interaction in melanopsin mediated photoresponses in vivo. In cultured cells we will test whether light activated melanopsin undergoes endocytosis and degradation and assess the role of melanopsin phosphorylation, and arrestin interaction in this process. Subsequently, we will develop strategies to specifically perturb gene expression in the mRGCs of adult mice. This approach will help evaluate the minimum threshold of melanopsin protein and melanopsin expressing ganglion cells required for normal non-image forming photoresponses. Using this ipRGC specific gene expression strategy we will perturb melanopsin phosphorylation by altering kinase activity or by expressing melanopsin with mutated phosphorylation sites. Next, we will assess melanopsin function in mice lacking individual beta-arrestins. Mice with perturbations in melanopsin phosphorylation, kinase activity or arrestin expression will be subject to various tests to evaluate light dependent melanopsin degradation, response kinetics of ipRGCs, and behavioral adaptation to light. Results from these experiments will illustrate the role of activity dependent phosphorylation of melanopsin in normal adaptation of behavior and physiology to light.

Public Health Relevance

The melanopsin expressing cells of the inner retina directly sense light and help the organism adapt its behavior and physiology to the ambient light. Experiments proposed in this application will help us understand how molecular events after light activation of melanopsin affects its overall signal properties and modulate behavioral adaptation to light.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Salk Institute for Biological Studies
La Jolla
United States
Zip Code
Chaix, Amandine; Zarrinpar, Amir; Miu, Phuong et al. (2014) Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab 20:991-1005
Hatori, Megumi; Gill, Shubhroz; Mure, Ludovic S et al. (2014) Lhx1 maintains synchrony among circadian oscillator neurons of the SCN. Elife 3:e03357
Mao, Chai-An; Li, Hongyan; Zhang, Zhijing et al. (2014) T-box transcription regulator Tbr2 is essential for the formation and maintenance of Opn4/melanopsin-expressing intrinsically photosensitive retinal ganglion cells. J Neurosci 34:13083-95
Pieraut, Simon; Gounko, Natalia; Sando 3rd, Richard et al. (2014) Experience-dependent remodeling of basket cell networks in the dentate gyrus. Neuron 84:107-22
Liu, Zhiwei; Huang, Moli; Wu, Xi et al. (2014) PER1 phosphorylation specifies feeding rhythm in mice. Cell Rep 7:1509-20
Clark, Daniel D; Gorman, Michael R; Hatori, Megumi et al. (2013) Aberrant development of the suprachiasmatic nucleus and circadian rhythms in mice lacking the homeodomain protein Six6. J Biol Rhythms 28:15-25
Jones, Kenneth A; Hatori, Megumi; Mure, Ludovic S et al. (2013) Small-molecule antagonists of melanopsin-mediated phototransduction. Nat Chem Biol 9:630-5
Park, Dongkook; Hadži?, Tarik; Yin, Ping et al. (2011) Molecular organization of Drosophila neuroendocrine cells by Dimmed. Curr Biol 21:1515-24
Xu, J; Cohen, B N; Zhu, Y et al. (2011) Altered activity-rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the ?2 nicotinic receptor. Mol Psychiatry 16:1048-61
DiTacchio, Luciano; Le, Hiep D; Vollmers, Christopher et al. (2011) Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333:1881-5

Showing the most recent 10 out of 20 publications