A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8

Abstract

To adapt to habitat temperature, vertebrates have developed sophisticated physiological and ecological mechanisms through evolution. Transient receptor potential melastatin 8 (TRPM8) serves as the primary sensor for cold. However, how cold activates TRPM8 and how this sensor is tuned for thermal adaptation remain largely unknown. Here we established a molecular framework of how cold is sensed in TRPM8 with a combination of patch-clamp recording, unnatural amino acid imaging, and structural modeling. We first observed that the maximum cold activation of TRPM8 in eight different vertebrates (i.e., African elephant and emperor penguin) with distinct side-chain hydrophobicity (SCH) in the pore domain (PD) is tuned to match their habitat temperature. We further showed that altering SCH for residues in the PD with solventaccessibility changes leads to specific tuning of the cold response in TRPM8. We also observed that knockin mice expressing the penguin's TRPM8 exhibited remarkable tolerance to cold. Together, our findings suggest a paradigm of thermal adaptation in vertebrates, where the evolutionary tuning of the cold activation in the TRPM8 ion channel through altering SCH and solvent accessibility in its PD largely contributes to the setting of the cold-sensitive/ tolerant phenotype.TRPM8 | cold activation | pore domain | side-chain hydrophobicity | thermal adaptation T o survive and thrive, all living beings have to perceive and adapt to ambient temperature (1), which varies over a wide range from below −50°C in polar areas to above 50°C in deserts (2). Therefore, sophisticated physiological and ecological mechanisms have been developed through evolution to first detect and then adapt to ambient temperature (3-5). The transient receptor potential melastatin 8 (TRPM8) channel is the prototypical sensor for cold in vertebrates (6, 7), which has been validated in both knockout mice (8) and pharmacological studies (9). However, how cold activates TRPM8 remains obscure. From the perspective of channel structure, an earlier study suggested that its C terminus is crucial for cold activation (10), while subsequent work demonstrated that the transmembrane core domain (5) or the pore domain (11) is essential for setting cold response. Although high-resolution structures of TRPM8 have been resolved by cryoelectron microscopy in both the apo and ligand-bound states (12-14), its coldactivated state structure is still unavailable. From the perspective of thermodynamics, large enthalpic (ΔH) and entropic (ΔS) changes are associated with TRPM8 cold activation (15,16). Changes in heat capacity have also been hypothesized to mediate cold activation (17), though experimental evidence for such a hypothesis is limited to voltage-gated potassium channels (18). Interestingly, cold activation of TRPM8 is tuned during evolution in several tested vertebrate species (5,11,19). To understand both the structural and thermodynamic bases of TRPM8 cold activation, we attempted to gain insights from TRPM8 orthologs in vertebrate species inhabiti...

Molecular mechanism underlying modulation of TRPV1 heat activation by polyols

“…2 , A and B ) or Mg 2+ ions ( 36 ) were perfused to the intracellular side of TRPV1, they exhibit little effects on its heat activation. Moreover, we found in the cold activated TRPM8 channel, residues modulating cold activation properties are all located in the outer pore region ( 48 ). Although theoretical analysis suggests that residues serving as temperature sensors in TRP channels can be widely distributed ( 23 ), our observation in this study with polyols and previous studies suggest a potential clustering of such residues to the outer pore of TRPV1.…”

The cool things to know about TRPM8!

“…The described molecular mechanisms will certainly have to be validated in larger animals and humans, particularly because of the species-specific sequence variation of TRPM8 that has been developed for thermal adaptation through evolution [ 13 ].…”

“…This channel is expressed in peripheral sensory neurons of small size (unmyelinated C fibers) to transduce environmental cold stimuli [ 7 , 11 , 12 ]. Notably, its ability to sense cold is finely tuned in various species for better ambient temperature adaptation [ 13 ] and by taking part in the energy metabolism [ 14 , 15 ]. In a recent study it has even been proposed that, along with TRPA1 and TRPV1 channels, TRPM8 underlies all thermosensation in mice [ 16 ].…”

Why wild giant pandas frequently roll in horse manure

“…More importantly, the regulation of TRPM8 has been identified to confer temperature adaptation in mammals throughout evolution (27,28). Since cold-activated TRPM8 is a major excitatory conduit for the decrease in temperature, physiological strategies have been employed by several vertebrates that tuned the cold activation of their own TRPM8 orthologs to achieve temperature adaptation (27)(28)(29). Almost without exception, however, these cases of developed temperature adaptation have only been discovered through the genetic evolution of molecular thermosensors.…”

“…These results indicate that BCPO acts as a potent inhibitor in the menthol-induced activation of gpTRPM8. Given that the temperature-activated gating process is likely distinct from the ligand-induced conformational change in TRP channels (28,32), we tested the cold-induced activation of gpTRPM8 in the absence or presence of BCPO. As shown in Fig.…”