10:31pm Friday 24 January 2020

Researchers find molecule that causes sunburn pain

130814-fuchs-sunburn2Blocking the molecule, called TRPV4, greatly protects against the painful effects of sunburn, according to a collaboration between Elaine FuchsLaboratory of Mammalian Cell Biology and Development at Rockefeller University and researchers at Duke University and the University of California, San Francisco. The research could yield a way to combat sunburn and possibly several other causes of pain.

“We see the effects of harmful sun rays to our body surface and we feel the pain associated. We now have a glimpse into how our epidermis instructs our brain to feel the pain,” says Fuchs, Rebecca C. Lancefield Professor at Rockefeller and a Howard Hughes Medical Institute investigator.

Feel the burn. Skin that had been chronically overexposed to UV rays showed elevated levels of TRPV4 (bottom left) and endothelin-1 (bottom right) as compared to normal skin. Researchers found that UVB exposure triggers the ion channel TRPV4 to release endothelin-1, a molecule known to cause pain, into the cell, contributing to the pain associated with sunburn.

The scientists investigated whether TRPV4, an ion channel which has been shown to be involved in other pain processes, might play a role in the pain and tissue damage caused by over-exposure to specific wavelengths of ultraviolet light, UVB. Although TRPV4 was discovered over 10 years ago at Rockefeller, the senior author, Duke’s Wolfgang Liedtke, had begun discussing its role in the epidermis with Dr. Fuchs only recently.

Together with colleagues, Dr. Liedtke and his team first built a mouse model that was missing TRPV4 only in the cells of the epidermis, the outermost layer of the skin. After exposing their hind paws — which most resemble human skin — to UVB rays, the researchers found that the mutant mice showed little sensitization and tissue injury compared with normal mice.

Next, they used cultured mouse skin cells to dissect the activities of TRPV4, which is an ion channel in the cell membrane. Using a device engineered by Nan Marie Jokerst, a professor at Duke’s Pratt School of Engineering, the researchers uncovered the sequence of events in this pain pathway: UVB exposure activates TRPV4, which causes the influx of calcium ions into the skin cells, which brings in another molecule called endothelin, which triggers TRPV4 to send more calcium into the cells. Endothelin is known to cause pain in humans and also evokes itching, which could explain the urge to scratch sunburned skin.

To see if they could block the pain pathway, the scientists used a pharmaceutical compound called GSK205 that selectively inhibits TRPV4. When applied to the hind paws of normal mice, the mice were resistant to the pain-inducing and skin-disrupting effects of sunburn. In mouse skin cells in culture, the compound stopped the UV-triggered influx of calcium ions into the cells.

“By blocking TRPV4 channels, our epidermis can no longer communicate with the sensory neurons in the skin,” says Fuchs. “Although this may not protect fully against the damage, it eases the pain.”

“Our understanding of how mammals respond to harmful UVB rays is altered, both at the molecular as well as the cellular level,” says Dr. Liedtke, associate professor of neurology and attending physician at the Duke Pain Clinics at Duke University Medical Center in Durham, North Carolina. “At the molecular level, TRPV4 is a key element of the UVB-sensing machinery in skin. At the cellular level, skin keratinocytes can sensitize the entire organism to feel the pathological pain of sunburn, which means a temporary re-programming of the pain-conducting organization of the central nervous system has been implemented as a result of TRPV4-signaling by skin keratinocytes.”

“The results position TRPV4 as a new target for preventing and treating sunburn, and probably chronic sun damage including skin cancer or skin photo-aging, though more work must be done before TRPV4 inhibitors can become part of the sun defense arsenal, perhaps in new kinds of skin cream, or to treat chronic sun damage,” said Martin Steinhoff, a dermatology professor at UCSF and co-senior author of the study.


13august-fuchs Proceedings of the National Academy of Sciences USA online: August 8, 2013
UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling
Carlene Moore, Ferda Cevikbas, H. Amalia Pasolli, Yong Chen, Wei Kong, Cordula Kempkes, Puja Parekh, Suk Hee Lee, Nelly-Ange Kontchou, Iwei Ye, Nan Marie Jokerst, Elaine Fuchs, Martin Steinhoff and Wolfgang B. Liedtke


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