The search for these temperature sensors began more than 20 years ago with the discovery of a heat-sensitive protein called TRPV1. Since then, proteins that detect hot, warm, and even cool temperatures have been found, but the one responsible for detecting temperatures below about 60 degrees Fahrenheit (15.5 degrees Celsius) remained elusive.

In a 2019 study, researchers from Xu’s lab discovered the first cold-sensitive receptor protein in a species of millimeter-sized worms called Caenorhabditis elegans. Since the gene that encodes this protein is evolutionarily conserved in many species, including mice and humans, this finding provided a starting point to verify the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2).

To test their hypothesis, the researchers conducted experiments on mice lacking the GluK2 gene, which means they couldn’t produce any GluK2 protein. They found that while the mice responded normally to warm, cool, and cold temperatures, they showed no response to harmful cold.

GluK2 is mainly found in neurons in the brain, where it receives chemical signals to facilitate communication between neurons. However, it is also expressed in sensory neurons of the peripheral nervous system (outside the brain and spinal cord). The researchers now know that this protein plays a completely different role in the peripheral nervous system, processing temperature signals instead of chemical signals to perceive cold.

Xu speculates that this temperature-sensing function may have been one of the protein’s original purposes, as the GluK2 gene has relatives throughout the evolutionary tree, dating back to single-celled bacteria. Since bacteria don’t have brains, it’s unlikely that they developed a way to receive chemical signals from other neurons. However, they would have a great need to perceive their environment, including both temperature and chemicals.

This discovery of GluK2 as a cold sensor in mammals opens up new avenues for better understanding why humans experience painful reactions to cold, and may even offer a possible therapeutic target for treating pain in patients whose sense of cold is overstimulated, such as those undergoing chemotherapy for cancer.

Researchers from the University of Michigan have identified the protein that allows mammals to feel cold, filling a long-standing gap in the field of sensory biology. This discovery could help us understand how we perceive and suffer from low temperatures in winter, and why some patients experience cold differently under certain disease conditions.

The search for these temperature sensors began more than 20 years ago with the discovery of a heat-sensitive protein called TRPV1. Since then, proteins that detect hot, warm, and even cool temperatures have been found, but the one responsible for detecting temperatures below about 60 degrees Fahrenheit (15.5 degrees Celsius) remained elusive.

In a 2019 study, researchers from Xu’s lab discovered the first cold-sensitive receptor protein in a species of millimeter-sized worms called Caenorhabditis elegans.

Since the gene that encodes this protein is evolutionarily conserved in many species, including mice and humans, this finding provided a starting point to verify the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2).

To test their hypothesis, the researchers conducted experiments on mice lacking the GluK2 gene, which means they couldn’t produce any GluK2 protein. They found that while the mice responded normally to warm, cool, and cold temperatures, they showed no response to harmful cold.

GluK2 is mainly found in neurons in the brain, where it receives chemical signals to facilitate communication between neurons. However, it is also expressed in sensory neurons of the peripheral nervous system (outside the brain and spinal cord).

The researchers now know that this protein plays a completely different role in the peripheral nervous system, processing temperature signals instead of chemical signals to perceive cold.

Xu speculates that this temperature-sensing function may have been one of the protein’s original purposes, as the GluK2 gene has relatives throughout the evolutionary tree, dating back to single-celled bacteria.

Since bacteria don’t have brains, it’s unlikely that they developed a way to receive chemical signals from other neurons. However, they would have a great need to perceive their environment, including both temperature and chemicals.

This discovery of GluK2 as a cold sensor in mammals opens up new avenues for better understanding why humans experience painful reactions to cold, and may even offer a possible therapeutic target for treating pain in patients whose sense of cold is overstimulated, such as those undergoing chemotherapy for cancer.


Sources

University of Michigan | Cai, W., Zhang, W., Zheng, Q. et al. The kainate receptor GluK2 mediates cold sensing in mice. Nat Neurosci (2024). doi.org/10.1038/s41593-024-01585-8


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