Opsins form a family of light-activated, retinal-dependent, G protein-coupled receptors (GPCRs) that serve a multitude of visual and nonvisual functions. Opsin 3 (OPN3 or encephalopsin), initially identified in the brain, remains one of the few members of the mammalian opsin family with unknown function and ambiguous light absorption properties. We recently discovered that OPN3 is highly expressed in human epidermal melanocytes (HEMs)-the skin cells that produce melanin. The melanin pigment is a critical defense against ultraviolet radiation (UVR), and its production is mediated by the Gαs-coupled melanocortin 1 receptor (MC1R). The physiological function and light sensitivity of OPN3 in melanocytes are yet to be determined. Here, we show that in HEMs, OPN3 acts as a negative regulator of melanin production by modulating the signaling of MC1R. OPN3 negatively regulates the cyclic adenosine monophosphate (cAMP) response evoked by MC1R via activation of the Gαi subunit of G proteins, thus decreasing cellular melanin levels. In addition to their functional relationship, OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures, and can form a physical complex. Remarkably, OPN3 can bind retinal, but does not mediate light-induced signaling in melanocytes. Our results identify a function for OPN3 in the regulation of the melanogenic pathway in epidermal melanocytes; we have revealed a light-independent function for the poorly characterized OPN3 and a pathway that greatly expands our understanding of melanocyte and skin physiology. opsin3 | encephalopsin | melanocytes | melanocortin 1 receptor | pigmentation U nlike most mammals, which have melanin-producing melanocytes predominantly in the hair follicle bulb (1), humans are uniquely equipped with melanocytes in the outermost layer of the skin, the epidermis (2, 3). These neural crest-derived melanocytes are the only source of the photoprotective pigment melanin in human skin, and thus are critical for the defense against solar ultraviolet radiation (UVR)-induced genotoxic damage (4-6).Solar UVR at the surface of the earth is composed of ∼5% short-wavelength UVB rays and ∼95% long-wavelength UVA rays. Much of our current knowledge about melanogenesis in epidermal melanocytes stems from the well-characterized UVBinduced melanin pathway (7). UVB elicits DNA damage in epidermal keratinocytes, triggering facultative skin darkening through increased melanin production in neighboring melanocytes (8). UVB-irradiated keratinocytes and melanocytes locally secrete α-melanocyte stimulating hormone (α-MSH), an agonist of the Gαs-coupled melanocortin 1 receptor (MC1R) that is primarily expressed on melanocytes (8,9). MC1R has a pivotal role in determining pigmentation, as several naturally occurring loss-offunction MC1R variants are associated with the redhead phenotype (10, 11) characterized by a pale complexion and increased sensitivity to UVR (12). Downstream, α-MSH-induced MC1R activation leads to stimulation of adenylyl cyclase (AC) and production of...
Because sunlight is essential for human survival, we have developed complex mechanisms for detecting and responding to light stimuli. The eyes and skin are major organs for sensing light and express several light-sensitive opsin receptors. These opsins mediate cellular responses to spectrally-distinct wavelengths of visible and ultraviolet light. How the eyes mediate visual phototransduction is well studied, but less is known about how the skin detects light. Both human and murine skin express a wide array of opsins, with one of the most highly expressed being the functionally elusive opsin 3 (OPN3). In this review we explore light reception, opsin expression and signaling in skin cells; and compile data elucidating potential functions for human OPN3 in skin, with emphasis on recent studies investigating OPN3 regulation of melanin within epidermal melanocytes.
Opsins form a family of light-activated, retinal-dependent G-protein coupled receptors (GPCRs) that serve a multitude of visual and non-visual functions. Opsin3 (OPN3 or encephalopsin), initially identified in the brain, remains one of the few members of the mammalian opsin family with unknown function and ambiguous light-absorption properties. We recently discovered that OPN3 is highly expressed in human epidermal melanocytes-the skin cells that produce melanin. The melanin pigment is a critical defense against ultraviolet radiation and its production is mediated by the Gs-coupled melanocortin-1 receptor (MC1R). The physiological function and light-sensitivity of OPN3 in melanocytes is yet to be determined.Here we show that in human epidermal melanocytes OPN3 acts as a negative regulator of melanin production by interacting with MC1R and modulating its cAMP signaling. OPN3 negatively regulates the cAMP response evoked by MC1R via activation of the Gαi subunit of G-proteins, thus decreasing cellular melanin levels. In addition to their functional relationship, OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures and form a physical complex. Remarkably, OPN3 can bind retinal, but does not mediate light-induced signaling in melanocytes. Our results identify a novel function for OPN3 in the regulation of the melanogenic pathway in epidermal melanocytes. Our results reveal a light-independent function for the poorly characterized OPN3 and a novel pathway that greatly expands our understanding of melanocyte and skin physiology. Key words:Opsin3 | Encephalopsin | Melanocortin 1 Receptor | Pigmentation | Human Epidermal Melanocyte SignificanceOur data reveals a novel function for the non-visual opsin OPN3 in regulating the pigmentation of human melanocytes by interacting with and modulating the activity of MC1R.
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