Cool Discovery: Menthol triggers cold-sensing protein

Incorporated into everything from pain-relieving creams to after-dinner mints, menthol elicits a pleasant cooling sensation on the skin or tongue. As a result, researchers have suspected that the chemical activates the same sensory receptors on cells that alert animals to cool temperatures.

Two research teams now confirm this hypothesis by independently reporting the discovery of a single cell-surface protein that enables sensory nerves to respond to both menthol and coldness. “This is the first cold receptor,” says Ardem Patapoutian of the Scripps Research Institute in La Jolla, Calif.

He and his colleagues describe their discovery in an upcoming issue of Cell. The second research group, headed by David Julius of the University of California, San Francisco, will publish a similar report in an upcoming issue of Nature.

The new research parallels the finding several years ago by Julius’ team that capsaicin, the substance that gives hot peppers their fiery kick, activates a receptor that senses heat (SN: 11/8/97, p. 297). The capsaicin-heat receptor and the menthol-cold receptor belong to the same protein family, the researchers report.

The discovery of the cold receptor “gives a boost to our hypothesis that molecules of this family are the primary sensors of thermal stimuli in the peripheral nervous system,” says Julius.

Patapoutian’s group sought a cold-sensing protein by searching DNA databases for genes related to the one encoding the capsaicin-heat receptor. In contrast, Julius and his colleagues created a library of genes active in cold- and menthol-sensitive nerves. They added the genes individually to menthol-insensitive cells until one enabled the cells to respond to the chemical, as evidenced by an inward surge of calcium ions.

Both groups ultimately identified the same gene; one encoding a cell-surface pore that regulates the flow of positively charged ions such as calcium into and out of a cell. In addition to making cells menthol-sensitive, this ion channel also opens when cells are exposed to cool temperatures, the researchers determined. Julius’ group found that cells with the receptor respond to temperatures ranging from 8 to 28C, whereas Patapoutian’s team reports that the receptor’s threshold is around 23C.

This discrepancy, as well as other subtle differences in the two groups’ findings, may simply reflect different assays used or different tissues tested. For example, Patapoutian and his colleagues conclude that cold-sensing nerves are distinct from heat-sensing nerves. But Julius’ team reports that about 50 percent of their nerve cells responded to both heat and cold.

Although there’s no direct evidence yet that menthol binds to the newfound ion channel, both research groups suggest that the chemical produces a cooling sensation by increasing the temperature threshold at which the receptor activates.

Other researchers praise the new findings but caution that more receptors and molecules are involved in sensing cold. “My gut feeling is that anyone who tries to explain cold [perception] based on a single mechanism or molecule is going to be wrong,” says Felix Viana of the Spanish Council for Scientific Research in San Juan de Alicante.

In support of that claim, he and colleagues will describe in the March Nature Neuroscience how the actions of multiple, unspecified ion channels allow sensory nerve cells to react to coldness.

Arthur Craig of the Barrow Neurological Institute in Phoenix also predicts that other cold receptors will be found. Cold-induced pain seems to be distinct from simple cold perception, he notes.

Still, Craig speculates that the new receptor’s discovery will lead to ways of treating cold allodynia, a condition in which people with nerve damage feel extreme pain from cool sensations, such as a breeze blowing across the skin.