A team of researchers from Duke University, Rockefeller University and the University of California San Francisco have identified the gene that causes pain in sunburned skin. In the Aug. 5 Proceedings of the National Academy of Sciences (PNAS) Early Edition online, the researchers find that blocking TRPV4 could allow humans to avoid sunburn pain.
The team investigated whether the TRPV4 molecule, which is abundant in skin cells and has been shown to be involved in other pain processes, might play a role in the pain and tissue damage caused by UVB over-exposure.
TRPV4 is an ion channel, a gateway in the cell membrane that rapidly lets in positively charged ions such as calcium and sodium. First, the researchers built a mouse model that was missing TRPV4 only in the cells of the epidermis, the outermost layer of the skin. They took these genetically engineered mice and their normal counterparts and exposed their hind paws--which most resemble human skin--to UVB rays. The hind paws of the normal mice became hypersensitive and blistered in response to the UVB exposure, while those of the mutant mice showed little sensitization and tissue injury.
Next, they used cultured mouse skin cells to dissect the activities of TRPV4. Using a device engineered by Nan Marie Jokerst, PhD, a professor of electrical and computer engineering at Duke's Pratt School of Engineering, the researchers showed that UVB caused calcium to flow into the skin cells, but only when the TRPV4 ion channel was present. Further molecular analysis uncovered the entire sequence of events in this pathway, with each event affecting the next: UVB exposure activates TRPV4, which causes the influx of calcium ions, 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 sunburned patients feel to scratch their skin.
To test whether these findings in mice and mouse cells have human relevance, the researchers used human skin samples to successfully demonstrate increased activation of TRPV4 and endothelin in human epidermis after UVB exposure. To see if they could block this novel pain pathway, the researchers used a pharmaceutical compound called GSK205 that selectively inhibits TRPV4. They dissolved this compound into a solution of alcohol and glycerol and then applied it to the hind paws of normal mice. The researchers found that the mice treated with the compound were again largely resistant to the pain-inducing and skin-disrupting effects of sunburn. Similarly, when they administered the compound to mouse skin cells in culture, they found that it stopped the UV-triggered influx of calcium ions into the cells.
The researchers believe that TRPV4 could be a new target for preventing and treating sunburn, but more work needs to be done. Specifically, the researchers want to make sure its inhibition does not affect other skin processes. Researchers noted that once better adapted, TRPV4 blockers could be added to UV filters for greater protection.
Researchers included: Wolfgang Liedtke, MD, PhD, Duke University School of Medicine; Elaine Fuchs, PhD, Rockefeller University and Howard Hughes Medical Institute; and Martin Steinhoff, MD, PhD, University of California in San Francisco. The research was supported by grants from the National Institutes of Health and the German Research Foundation.