New research is homing in on the biochemical mechanisms that allow mammals to feel cold.

The study is the first to identify a protein that responds to extreme cold. The gene is evolutionarily conserved across species, including humans.

Chilly

“Clearly, nerves in the skin can sense cold. But no one has been able to pinpoint exactly how they sense it,” said Shawn Xu, a faculty member at the University of Michigan Life Sciences Institute and senior author of the study. “Now, I think we have an answer.”

It’s vital for our bodies to be able to perceive temperature. When it gets too chilly outside, we need to feel that uncomfortable ‘cold‘ sensation so that we’ll seek shelter, warmth, and not die from exposure.

It falls to receptor proteins in the nerves of our skin to perceive this change and then relay the information to our brains. This mechanism holds true from humans down to very simple organisms, such as the millimeter-long worms that researchers study in Xu’s lab at the Life Sciences Institute: Caenorhabditis elegans.

We seek warmer environments when we’re cold, and Xu’s worms do the same thing: when they sense cold, they engage in avoidance behavior and move away, seeking warmth. However, unlike us, C. elegans have a simple and well-mapped genome, and a short lifespan, making them a valuable model system for studying sensory responses.

Previous efforts to find the receptor for cold have been unsuccessful because researchers were focusing on specific groups of genes that are related to sensation, which is a biased approach, Xu said. Instead, he and his team relied on the simplicity of C. elegans for an ‘unbiased approach’.

The team looked across thousands of random genetic variations to determine which affected the worms’ responses to cold. They report that worms engineered to lack the glutamate receptor gene glr-3 no longer responded when temperatures dipped below 18 degrees Celsius (64 F).

Glr-3 is responsible for making the eponymous GLR-3 receptor protein; without this protein, the worms lost sensitivity to cold temperatures, a strong indicator that it underpins the ability to sense cold.

The glr-3 gene is evolutionarily conserved across species including humans. The vertebrate versions of the gene can also function as a cold-sensing receptor, the team adds. The team determined this after adding the mammalian version of the gene to mutant worms lacking glr-3 (and were thus insensitive to cold), which made them feel cold temperatures once more.

The team also added the worm, zebrafish, mouse, and human versions of the genes to cold-insensitive mammalian cells, and all allowed the cells to sense to cold temperatures.

The mouse version of the gene, GluK2 has been documented to help transmit chemical signals within the brain. The authors further discovered that the gene is also active in a group of sensory neurons that detect environmental stimuli, such as temperature, through sensory endings in the mice’s skin. Reducing expression of GluK2 in these sensory neurons made the mice insensitive to cold, but not cool, temperatures — additional evidence that the GluK2 protein serves as a cold receptor in mammals.

“For all these years, attention has been focused on this gene’s function in the brain. Now, we’ve found that it has a role in the peripheral sensory system, as well,” Xu said. “It’s really exciting. This was one of the few remaining sensory receptors that had not yet been identified in nature.”

The paper “A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene” has been published in the journal Cell.