Researchers at the University of California San Francisco have discovered a receptor protein in rodents and humans tuned to respond to temperatures of 120 degrees Fahrenheit and higher - by far the hottest temperatures for which a nerve receptor has been identified.
The protein may be part of a network of mammalian nerve receptors coordinated to detect a wide range of temperatures, but it almost certainly has other as-yet-unknown functions, the researchers report in the current issue of the journal Nature.
The discovery was made as a result of searching the bank of known human gene sequences for a close match to the protein that responds to capsaicin, the molecule that gives hot peppers their bite. Two years ago, the same research team identified the capsaicin receptor, which enables us to detect the heat of chili peppers, as well as temperatures of around 100 degrees.
"While the capsaicin receptor is a very exclusive protein, restricted to sensory nerves, this new protein is more of a generalist," said David Julius, Ph.D., senior author on the Nature paper and associate professor of cellular and molecular pharmacology at UCSF. "It is found on sensory nerves as the capsaicin receptor is, but we also found evidence of it in the brain and spinal cord, in the spleen and intestines. Clearly, in these sites it must be responding to something other than temperature."
Whatever the full function of VRL-1, its discovery holds promise for better understanding pain and developing drugs to block pain, Julius said. "The number of targets to relieve pain is limited. Any discovery of a receptor for extreme temperatures or other noxious stimuli broadens the range of targets for which you can develop candidate drugs."
With the knowledge they have gained of the receptor's gene sequence, the scientists can start to study its function, a major boost to the effort to develop new drugs against pain.
The receptor, known as VRL-1, may respond to some stimulus other than temperature, Julius said, such as a change in a chemical concentration critical to cells in non-sensory sites. And it may also respond to temperature when associated with sensory nerves.
"This receptor is in too many places in the body for us to really take a good guess right now at what it might be responding to other than heat. It is a generalist in some way that we don't yet understand, and no one has identified the molecular players in this process."
UCSF postdoctoral scientist Michael J. Caterina, M.D., Ph.D., made the discovery along with other members of the Julius lab and is first author on the Nature paper.
"VRL-1 may be acting in concert with other receptors tuned to other temperatures to cover a broad range, much as visual pigment receptors are tuned to different wavelengths, allowing us to see a range of colors," said Caterina. "It may be hard (for evolution) to design a single protein that can respond linearly to a wide range of noxious temperatures."
Co-authors with Julius and Caterina are Tobias A. Rosen, B.S., a postgraduate research associate, Makoto Tominaga, M.D., Ph.D., a postdoctoral scientist, and Anthony J. Brake, Ph.D., senior research associate.
The research is supported by the National Institutes of Health.
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