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Developmental Biology - Proteins

A Protein That Adjusts Skin Color

After a series of surprising discoveries, scientists determine the protein opsin 3 adapts human skin color...

When humans spend time in the sun without proper skin protection, ultraviolet (UV) radiation signals skin melanocytes to over produce melanin. Melanocytes make skin appear darker as they spread out to protect skin against UV rays that cause cancer. There are two parts to solar radiation: (1) UVB or short wavelength and (2) UVA or long wavelength. Each is detected by skin cells in slightly different ways.

How UVB makes humans tan has been known for a while. But, scientists know less about how skin detects and responds to UVA, the most abundant solar radiation. In 2017, Nicole Y. Leung and Craig Montell published in the Annual Review of Cell and Developmental Biology, their discovery in fruit flies that opsins do not function exclusively as light sensors. They documented opsins also are pivotal in temperature sensation and hearing.

In this current work, Elena Oancea PhD, associate professor in the department of Molecular Pharmacology, Physiology and Biotechnology at Brown University, and her team better define the role of opsin yet again. In 2015 Oancea's team uncovered the first clues to indicate melanocytes, skin cells that produce melanin pigment, have an abundance of the protein opsin 3. This led her team to theorize opsin 3 might be the receptor detecting UVA and signalling for an increase in melanin.

Four years and four major surprises later, Oancea's team published May 16, in the journal Proceedings of the National Academy of Sciences or PNAS, an additional opsin discovery.
"We've observed the role of opsin 3 in human melanocytes and figured out the molecular steps that allow it to achieve this function. Opsin 3 modulates how much pigment skin cells make, but, surprisingly, it does so independent of light. This mechanism is a new paradigm for opsin. Once we learn more about opsin 3, it may be a good target for treating pigmentation disorders."

Elena Oancea PhD, Associate Professor, Medical Science, Brown University, Providence, Rhode Island, USA.

To verify their observation, team member Rana Ozdeslik PhD, used a genetic engineering tool to greatly reduce the amount of opsin 3 in cultured human melanocyte cells. These skin cells, almost devoid of opsin 3, were then exposed to UV light. Surprisingly, the cells still responded by producing a burst of calcium ions. Their initial hypothesis was wrong. Explains Oancea: "Our first big surprise was opsin 3 is not a UVA detector."

Even without opsin 3, the skin cells appeared much darker. When measured, the melanocytes had produced more pigment in the absence of opsin 3. This was the team's second surprise.
Opsin 3 Properties To Date
(1) A molecular signal triggering melanin
(2) Changes melanocortin-1 to increase cAMP
(3) Can also decrease levels of cAMP
(4) Binds to retinal, a light sensor

Oancea believes it is possible retinal either serves some kind of structural purpose or that opsin 3 absorbs light at a wavelength not easily measurable. Ultimately, the team determined that opsin 3 decreases melanin production in skin cells by decreasing levels of an important molecular signal and not one triggered by light.

The finding that opsin 3 can adjust how much pigment melanocytes make, suggests it could be a target for treating hyper-pigmentation disorders characterized by too much melanin; and hypo-pigmentation disorders such as albinism, characterized by too little melanin. Most pigmentation disorders have no available treatments.

Before scientists target opsin 3 in skin, they have to understand exactly what it does in other parts of the body, and be able to modify its activity. In 2016 it was found in the chicken retina and brain, work published in PLOS.
The research team is now seeking opsin 3 in other parts of the body to find if there are other properties it might have.

This study expands understanding of opsin 3 (OPN3) function and of skin pigmentation. The findings presented here reveal that the nonvisual OPN3 modulates the pigmentation of human epidermal melanocytes the melanin producing cells of the skin by controlling the activity of the main pigmentation receptor, melanocortin 1 receptor (MC1R). The study identifies an OPN3 function in regulating human skin pigmentation via a unique molecular mechanism; it also reveals a regulatory mechanism for MC1R in melanocytes. These results advance our understanding of nonvisual opsins and their extraocular role; they also represent a paradigm for OPN3 function via modulation of MC1Rs activity. These findings set the stage for future investigations of OPN3 function in other tissues.

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 Gas-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 G?i 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.

Rana N. Ozdeslik, Lauren E. Olinski, Melissa M. Trieu, Daniel D. Oprian and Elena Oancea.

This research was supported by National Institutes of Health (grant numbers R01 AR066318 and T32 GM077995), the Suna and Inan Kirac Foundation, as well as internal funding from Brown University.

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May 22 2019   Fetal Timeline   Maternal Timeline   News  

A team of Brown University scientists find opsin 3 - a protein closely related to light sensitive
rhodopsin protein which enables low-light vision - adjusts pigmentation in human skin.
Credit: Oancea laboratory, Brown University, Providence, Rhode Island, USA.

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