The Molecular Mechanism of Ultraviolet Phototransduction in Human Melanocytes (2012 - Present)

Investigator:  Elena Oancea, Brown University
Mentor:  Julie Kauer, Brown University

Abstract:  Skin, the largest organ of the human body, is constantly exposed to solar ultraviolet radiation (UVR), a powerful environmental risk factor for skin cancer.  Human skin has the unique protective ability among vertebrates to increase its pigmentation upon UVR exposure due to melanin production in epidermal melanocytes.  When this defense mechanism is inefficient, as in fair-skinned people, or in response to prolonged UVR-exposure, cancer-promoting genotoxic damage occurs.  How does human skin sense and respond to UVR?  Despite ample research characterizing effects of UVR on skin, our understanding of the mechanisms underlying the skin's ability to sense and respond to UVR remains incomplete.  To investigate the molecular pathways mediating cellular responses to UVR, we have designed a setup that allows simultaneous UVR stimulation and real-time imaging of cultured dells.  Stimulation of melanocytes with physiological doses of UVR initiates a transient calcium response that is consistent with activation of a photosensitive G protein coupled receptor.  Using our UVR/imaging setup in combination with molecular and biochemical techniques, we will test our hypothesis that UVR-induced intracellular calcium responses are mediated by activation of an opsin receptor coupled to a G protein, which stimulates phospholipase C (PLC) and generates diacylglycerol (DAG) and inositol (1,4,5) trisphosphate (IP3), which leads to calcium release from the internal stores.  These studies will identify and characterize a novel UVR phototransduction pathway and determine its function in skin; this mechanism will significantly advance our understanding of melanocyte function and of the skin's response to solar UVR.  The results of the proposed experiments will provide a foundation for further studies exploring links between UVR and cancer, and might uncover novel mechanisms involved in pigmentation disorders and skin cancer.  Our findings will have a broad impact on characterizing novel, non-visual functions for ospin receptors, and on understanding mechanisms of light sensing and signaling in human skin.