Molecular Prerequisites for Diminished Cold Sensitivity in Ground Squirrels and Hamsters

Thirteen-lined ground squirrels and Syrian hamsters are known for their ability to withstand cold during hibernation. We found that hibernators exhibit cold tolerance even in the active state. Imaging and electrophysiology of squirrel somatosensory neurons reveal a decrease in cold sensitivity of TRPM8-expressing cells. Characterization of squirrel and hamster TRPM8 showed that the channels are chemically activated but exhibit poor activation by cold. Cold sensitivity can be re-introduced into squirrel and hamster TRPM8 by transferring the transmembrane domain from the cold sensitive rat ortholog. The same can be achieved in squirrel TRPM8 by mutating only six amino acids. Reciprocal mutations suppress cold sensitivity of the rat ortholog, supporting functional significance of these residues. Our results suggest that ground squirrels and hamsters exhibit reduced cold sensitivity, partially due to modifications in the transmembrane domain of TRPM8. Our study reveals molecular adaptations that accompany cold tolerance in two species of mammalian hibernators. [Display omitted] •Squirrels and hamsters are cold tolerant even in active, non-hibernating state•Cold tolerance in hibernators is partially supported by somatosensory system•Squirrel and hamster somatosensory neurons express cold-insensitive TRPM8•Cold sensitivity of squirrel TRPM8 channel is back-engineered by six mutations Matos-Cruz et al. show that ground squirrels and hamsters exhibit cold tolerance even in the active non-hibernating state, partially due to independent modifications in the core transmembrane domain of the cold-sensing channel, TRPM8. The study reveals molecular adaptations that accompany cold tolerance in two species of active mammalian hibernators.