Circadian Photoentrainment in Mammals

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DESCRIPTION (provided by applicant): In mammals, a master circadian clock in the suprachiasmatic nucleus of the hypothalamus synchronizes metabolism, cardiac output, alertness, and sleep state with the daily light/dark cycle. Chronic desynchronization of the circadian clock is a significant contributor to metabolic diseases, as well as sleep and mood disorders. Even temporary desynchronization of the clock with the natural day:night cycle, such as in jet lag or shift work syndrome, is a leading cause of productivity loss and accidental injury or death. Thus, a firm understanding of circadian clock function that leads to treatment of related disorders will lead to health and economic benefits of the society. Synchrony of the clock with the external environment is largely governed by exposure to light received by the eye. However, the precise mechanism by which light entrains the circadian oscillator is not known. An intriguing feature of circadian light entrainment is its resistance to several physiological conditions and mutations that usually causes blindness. This suggested novel photopigment, signaling property and chromophore use may be involved. Recently, a new opsin-like photopigment, melanopsin, was found in the inner retina and has been established as a dominant mediator of light input to the circadian clock. Experiments proposed in this project are to understand some key aspects of melanopsin's photosensitivity. Specifically, we want to understand the spectral and photochemical properties of melanopsin and how its interaction with arrestin modulates such function. We have developed heterologous expression systems for the measurement of melanopsin photosensitivity in living cells and for high level expression of the opsin for biochemical analysis. Using both cellular and biochemical assays we will (a) determine whether melanopsin photopigment exists in two distinct spectrally active and photoreversible states, (b) whether melanopsin has an intrinsic photoisomerase activity to regenerate its own chromophore and (c) how interaction with arrestin determines its photochemical properties. Successful completion of these aims will identify key functional features of melanopsin phototransduction, elucidate the underlying mechanism, and provide potential entry points for therapeutic intervention in circadian disorders.