A team of researchers at Brown University found that opine 3, a protein closely related to rhodopsin, the protein that allows low-light vision, has a role in regulating the amount of pigment produced in human skin that defines the color of the skin.
When people spend their time in the sun without adequate skin protection, sun UV (UV) radiation signals the skin to produce more melanin – which prevents the cancer-causing effects of radiation – and becomes darker. There are two parts for solar ultraviolet radiation: short wavelength or UVB and wavelength or UVA. Each part is detected by the skin in different ways; how UVB makes people tan is known for some time.
On the other hand, scientists know less about how skin discovers and reacts to UVA, the richest species of solar ultraviolet radiation. Elena Oancea, an associate professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown, studies exactly this question. In 2015, when her team found the first evidence that melanocytes, the specialized skin cells that produce pigment melanin, have plenty of opsin 3, they believe that opine 3 can be a receptor that detects UVA and signals increase the production of melanin.
Four years and four big surprises later the team's findings were published on Thursday, May 16, in the magazine Notifications of the National Academy of Sciences,
"We have discovered the role of opsin 3 in human melanocytes and we have understood the molecular steps that allow opine 3 to achieve this function," Ochancha said. "Opsin 3 modulates how much pigment the cells do, but, surprisingly, it does it regardless of light.This mechanism is a new paradigm for opines.When we learn more about opine 3, it can be a good goal to treat pigmentation disorders.
Armed with its initial hypothesis that opse 3 detects UVA radiation, causing calcium ions to flood melanocytes and trigger melanin production, the team jumped into experiments. Rana Ozdeslik, a doctoral student who is a PhD. by Brown in 2017, and continued work on the project as a researcher using a genetic engineering tool to dramatically reduce the amount of opine 3 in cultured human melanocytes.
When Ozdeslik exposed the skin to cells with almost no opine 3 of UV light, they still produced a calcium ion burst. Their original hypothesis was wrong.
"Our first major surprise was that opsin 3 is not a UVA detector," Ochancha said.
While the team was planning the next steps, Ozzlikick noticed that skin cells without opine 3 seemed much darker, said Ochancha. This was the second surprise. In fact, when they measure melanin, melanocytes have made more pigment in the absence of opine 3. The next step is to understand how.
At this point in the research process to the team joined the Doctor of Brown Loren Olinski. Together, they discovered that opine 3 alters the activity of the melanocortin-1 receptor, a protein known to increase cyclic adenosine monophosphate synthesis (cAMP), a molecular signal triggering melanin production. Opsin 3 regulates melanin by decreasing cAMP levels produced by the melanocortin-1 receptor. This was the third surprise of the project.
The team found that, as expected, opine 3 binds the retina, a form of vitamin A, which is essential for traceability of light in all rhodopsin-related proteins. However, they can not find opine 3, absorbing any wavelength of light. It was their fourth surprise and the one that Oancha still finds quite puzzling. She said it was possible for the retina to serve some structural purpose, or that opsin 3 absorbed light in a wavelength range that can not be readily measured.
Eventually, the team found that opine 3 reduces the production of melanin in the skin cells, reducing the levels of an important molecular signal – but this regulation does not appear to be triggered by light.
Now that they have established the role of opsin 3 in skin pigmentation, the team is trying to learn what other parts of the body are produced and what features they can have. Olsen works to determine where and how he works in the brain where he was first discovered.
The discovery that opine 3 can correct the amount of pigment melanocytes suggests that opine 3 may be a target for the treatment of pigmentation disorders. Hyperpigmentation disorders are characterized by too much melanin; Hypopigmentation disorders, such as albinism, are characterized by too little melanin, which significantly increases patients' sensitivity to solar ultraviolet radiation and sensitivity to skin cancer. Most pigmentation disorders have no treatments available. Before scientists can turn to opine 3 in the skin, they need to understand what they are doing in other parts of the body and learn how to turn on or off their activity, says Oancea.
Besides Oancea, Ozdeslik and Olinski, other authors of the article include Melissa Trie and Daniel Oprean of the University of Brandes.
This study is supported by National Institutes of Health (grants R01 AR066318 and T32 GM077995), Suna Foundation and Inan Kirac, as well as internal funding from Brown University.