Researchers at Columbia University have produced detailed images of a molecule in the skin that can sense temperature. This work, which shows the receptor in closed, open and intermediate states, can now help scientists learn more about how various temperatures are detected, and will aid in the development of therapeutics that can treat chronic itch, pain, and inflammatory disease in the skin. The findings have been reported in Nature Structural and Molecular Biology.
Special sensory neurons are involved in the perception of pain and temperature, and we’ve known that for more than one hundred years. Several decades ago, a large family of molecules was identified, transient receptor potential (TRP) channels, and eleven of them are sensitive to temperature changes. As temperature fluctuates, these ‘thermoTRPs’ open or close in response, and ions can send signals to the nervous system as they move in and out of them.
"ThermoTRPs act as biological thermometers, allowing organisms to sense temperatures in the entire physiological range, from noxious cold to noxious heat," explained study leader Alexander I. Sobolevsky, Ph.D., an associate professor of biochemistry and molecular biophysics at Columbia University Vagelos College of Physicians and Surgeons. "How these channels sense temperature and then subsequently undergo changes at the molecular level has remained a puzzle."
Cryo-electron microscopy was applied several years ago to reveal the structure of some of these TRP channels, and nearly every channel has been subsequently imaged in the same way. However, the structure of the channels at various temperatures remained elusive, especially the form of channels that sense heat at high temperatures.
One of these channels, TRPV3 is found primarily in skin cells. It not only senses temperature, but it also senses harmful stimuli, helps maintain the skin as a barrier, and is involved in wound healing and hair growth. It has been linked to several diseases that impact the skin including psoriasis, rosacea, and atopic dermatitis. In a mouse model, if TRPV3 is absent, they can’t sense warmer temperatures.
In the new research, Sobolevsky's team found a mutation in the TRPV3 channel that enabled them to visualize the channel in different positions as it responded to various temperatures. They have shown how TRPV3 changes its structure as heat activates it.
"These structural changes seem to originate from the ion-conducting membrane portion of TRPV3 that senses temperature through its interaction with the surrounding membrane lipids," explained study first author Appu K. Singh, Ph.D., an associate research scientist in biochemistry and molecular biophysics at Columbia University. "Further studies are needed to identify the temperature sensor of these channels more precisely."
"Our structures not only can serve as a springboard for studies of the biophysical principles of ion channel temperature activation, but also as templates for the design of drugs for a variety of conditions that affect the skin," added Sobolevsky.