Shape of structure that nerve cells use to sense cold and menthol could be new target for chronic pain and migraine

February 7, 2019, Duke University
An ion channel in human nerve cells called the transient receptor potential melastatin member 8 (TRPM8) senses both coldness and menthol, transmitting cooling sensations by releasing calcium (green spheres). Credit: Ying Yin, Duke University

People are great at detecting cold temperatures and also the cool sensation induced by natural substances like menthol, which is common in remedies used to soothe aching muscles. But it hasn't been entirely clear how we do this.

About a year ago, a group of researchers led by Seok-Yong Lee, Associate Professor of Biochemistry in the Duke University School of Medicine, figured out the architecture of the human and animal cold-sensing protein, an called TRPM8, which gave them some insight into its function but also raised more questions.

Now, Lee's team has determined the structure TRPM8 assumes when it is bound to and to another synthetic cooling agent called icilin. The findings, which will appear in Science on Feb. 8, could pave the way toward new treatments for and migraine and help patients who suffer from extreme cold sensitivity.

In an attempt to better understand TRPM8, Lee and colleagues used a technique called (cryo_EM), which is new to Duke.

The strategy involves purifying the protein from cells, flash freezing it, and then bouncing electrons off of the sample embedded in ice in a giant machine called a Titan Krios. The cryo-EM made a composite of images of more than a million protein particles in various orientations and then computed a high-resolution three-dimensional structure for TRPM8.

The trickiest part, according to Lee, was finding a version of the protein that would be stable enough to visualize its structure. The most success they had was with TRPM8 channels from a small, black and white bird called the collared flycatcher, which has channels similar to human TRPM8. They generated and isolated the protein in the lab, then mixed it with either menthol or icilin and PIP2 (phosphatidylinositol 4,5-bisphosphate), a lipid molecule that sends signals within cells and has been previously shown to be necessary for TRPM8 to properly sense both menthol and icilin.

The team found that the spot in TRPM8 where menthol and icilin bind is adjacent to the for PIP2. The close proximity of these binding locations suggests that PIP2 and the cooling agents likely cooperate to control structural changes in TRPM8 that allow it to signal cold-sensing by sending electrical signals to the brain, but that's still an open question.

"We figured out menthol binding to TRPM8, and we have some clue about how this channel opens, but we still don't fully understand how this menthol binding is coupled to the channel opening," said Lee, adding that his group plans to focus on how the channel opens in the future.

Nevertheless, he said, this and future steps toward gaining a greater understanding of how TRPM8 works is important because the is also the target of painkillers, including topical remedies that contain menthol. While activating it typically leads to pain relief, in some cases like cold allodynia, where minor sensations such as a few drops of cold water on the skin can cause pain, turning the off could have benefits.

Explore further: Menthol receptor also important in detecting cold temperatures

More information: "Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel" Science (2019). … 1126/science.aav9334

Related Stories

Menthol receptor also important in detecting cold temperatures

June 7, 2007

The ion channel activated by menthol also detects a wide range of cold temperatures and relays the information to the brain, according to a study in Nature by Yale School of Medicine, the University of California at San Francisco, ...

Why menthol chills your mouth when it's not actually cold

January 22, 2015

Try putting an ice-cube in your mouth. The insides of your mouth and tongue instantly turn numb. Hold it in still and you will feel pain. Now try sucking on peppermint. The mint itself is at room temperature, but your mouth ...

The sensation of cold is shut down by inflammation

July 2, 2012

(Medical Xpress) -- Research groups at the University of Cambridge and the Instituto de Neurociencias, in Spain, have discovered a new and unexpected mechanism by which cold sensation is regulated, and opens up the possibility ...

Neuroscientists map brain's response to cold touch

June 18, 2018

Carnegie Mellon University neuroscientists have mapped the feeling of cool touch to the brain's insula in a mouse model. The findings, published in the June 15 issue of Journal of Comparative Neurology, provide an experimental ...

Recommended for you

Archaeologists discover Incan tomb in Peru

February 16, 2019

Peruvian archaeologists discovered an Incan tomb in the north of the country where an elite member of the pre-Columbian empire was buried, one of the investigators announced Friday.

Where is the universe hiding its missing mass?

February 15, 2019

Astronomers have spent decades looking for something that sounds like it would be hard to miss: about a third of the "normal" matter in the Universe. New results from NASA's Chandra X-ray Observatory may have helped them ...

What rising seas mean for local economies

February 15, 2019

Impacts from climate change are not always easy to see. But for many local businesses in coastal communities across the United States, the evidence is right outside their doors—or in their parking lots.

The friendly extortioner takes it all

February 15, 2019

Cooperating with other people makes many things easier. However, competition is also a characteristic aspect of our society. In their struggle for contracts and positions, people have to be more successful than their competitors ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.