As an ice cream melts in your mouth this summer, take a moment to contemplate the protein that may be bringing you that sense of cool relief - and numbing your tongue. Researchers have pinned down that particular protein in mice, and think that a similar one in humans does the same job.

Three papers, two published recently in Neuron and the third in this week's issue of Nature, have shown that mice rely on a single protein, called TRPM8, to sense both cold temperatures and menthol, the compound that gives mints their cool sensation.

The sensor also controls the pain-relieving effect of cool temperatures, but does not seem to play an important role in the response to painfully cold temperatures below 10 °C

TRPM8 is in the same family as the protein that detects heat and capsaicin, the compound that makes peppers hot. These proteins lie in the cell membranes of select neurons, and form channels that open and close in response to external signals.

Both cold temperatures and menthol trigger TRPM8 to open, allowing small, positively charged molecules, such as calcium ions, to pour into the cell.

Mice and humans each contain the gene that codes for TRPM8. In the lab dish, both versions open their channel when temperatures dip below 27 °C. Now, three teams have independently created mutant mice that cannot produce the TRPM8 protein.

Cold comfort

All three found that the mice became almost entirely insensitive to mild cold temperatures and methanol, although a slight residual response suggested the presence of a much weaker pathway not involving TRPM8.

David Julius of the University of California, San Francisco, and his colleagues, also directly tested cold responses by measuring electrical changes in nerves at the skin. The mutant mice, they found, showed almost no response1.

Demonstrating this activity in live animals was critical to firmly establishing TRPM8's dominant role in sensing cold temperatures, says neurobiologist Emily Liman of the University of Southern California, Los Angeles. "This one ion channel can explain nearly everything about detection of innocuous cold," she says.

Cold can also numb the skin, relieve pain, and combat inflammation. To find out if TRPM8 was involved in cold-induced pain relief, Ardem Patapoutian of the Scripps Research Institute in La Jolla, California and his colleagues injected their mice with a painful compound, put them on a cold plate and measured the amount of time the mice spent flinching their hind legs in response to the pain.

The mutant mice flinched more, showing that TRPM8 is also responsible for cold-induced pain relief.2 "It was very striking," says Patapoutian of the results.

Cold remedy


The protein also seems to be involved in a condition called 'cold allodynia' in which patients become hypersensitive to cold temperatures. Ning Qin, of Johnson & Johnson's pharmaceutical research and development lab in Pennsylvania, and his colleagues surgically induced the condition in their mice and then measured the animals' response to cold. Mice without TRPM8 lacked the cold sensitivity caused by the condition3.

"Without TRPM8, the mouse doesn't feel it," says Qin. Drugs that target TRPM8 might be able to treat cold allodynia, he says.

These results are promising, says Michael Caterina, a neurobiologist at the Johns Hopkins School of Medicine in Baltimore, Maryland. But, he says, cold responses are complex and more work will need to be done before we'll know if targeting TRPM8 is the right approach to take.

"There's going to be a complex set of cold-evoked signals that reach the central nervous system," he says. "It's hard to say right now if a drug that blocks TRPM8 is going to have a negative or positive effect."