Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels

Abstract

The ability to sense heat is crucial for survival. Increased heat tolerance may prove beneficial by conferring the ability to inhabit otherwise prohibitive ecological niches. This phenomenon is widespread and is found in both large and small animals. For example, ground squirrels and camels can tolerate temperatures more than 40°C better than many other mammalian species, yet a molecular mechanism subserving this ability is unclear. Transient receptor potential vanilloid 1 (TRPV1) is a polymodal ion channel involved in the detection of noxious thermal and chemical stimuli by primary afferents of the somatosensory system. Here, we show that thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and Bactrian camels (Camelus ferus) express TRPV1 orthologs with dramatically reduced temperature sensitivity. The loss of sensitivity is restricted to temperature and does not affect capsaicin or acid responses, thereby maintaining a role for TRPV1 as a detector of noxious chemical cues. We show that heat sensitivity can be reengineered in both TRPV1 orthologs by a single amino acid substitution in the N-terminal ankyrin-repeat domain. Conversely, reciprocal mutations suppress heat sensitivity of rat TRPV1, supporting functional conservation of the residues. Our studies suggest that squirrels and camels co-opt a common molecular strategy to adapt to hot environments by suppressing the efficiency of TRPV1-mediated heat detection at the level of somatosensory neurons. Such adaptation is possible because of the remarkable functional flexibility of the TRPV1 molecule, which can undergo profound tuning at the minimal cost of a single amino acid change.TRPV1 | thermosensation | thirteen-lined ground squirrel | bactrian camel | sensory physiology T he somatosensory system allows animals to distinguish between innocuous and noxious temperatures, guiding them to environments most amenable for life and reproduction. In general, mammals avoid contacting surfaces heated more than 40°C, which helps stave off the danger of tissue damage, but at the same time limits inhabitable areas. Mammalian extremophiles such as camels and diurnal rodents, including ground squirrels and chipmunks (Fig. 1A), thrive under thermal conditions that are harmful or even fatal to other animals. The mechanism(s) that allows such species to cope with high temperatures are complex and involve various organs and tissues, including thermoregulatory and somatosensory systems (1-5), but the exact molecular adaptations remain enigmatic.In rodents, noxious stimuli, including temperature, are detected in the skin by the terminal endings of C-type nociceptors from dorsal root or trigeminal ganglia marked by the expression of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) (6-9). Deletion of Trpv1 in mice does not abolish pain sensitivity in general (10) but diminishes sensitivity to noxious temperatures more than 50°C (7,8). Whereas the general pathways of heat sensitivity in standard laboratory rodents has been worked out in some...

Molecular Prerequisites for Diminished Cold Sensitivity in Ground Squirrels and Hamsters

“…We characterized temperature sensitivity of active ground squirrels and hamsters (Figure 1A) using a two-plate temperature preference test (Laursen et al 2016). We quantified the time spent by the animals on a reference plate set at 30°C or a test plate set to a temperature range from 0°C to 30°C.…”

“…Recently, we reported that ground squirrels are tolerant to noxious heat, partially due to diminished heat sensitivity of the TRPV1 channel in peripheral nociceptors (Laursen et al 2016). Similar to TRPM8, the suppression of temperature sensitivity in squirrel TRPV1 is specific, as the channel remains sensitive to chemical agonists, such as protons and capsaicin, preserving its role in inflammation.…”

Somatosensory Neurons Enter a State of Altered Excitability during Hibernation

“…These processes are energetically expensive, underscoring the notion that torpor is an active physiological process that requires molecular fine-tuning. Indeed, recent studies in hibernating rodents revealed profound genomically encoded changes in temperature sensors, mitochondrial function, protein control machineries, and cytoskeletal integrity [5, 6, 33]. We suggest the existence of other such modifications in various groups of enzymes, ion channels, and transporters implicated in energy homeostasis and ionic balance regulation.…”

Expression and Purification of the Pain Receptor TRPV1 for Spectroscopic Analysis

“…For example, Voets et al suggested that temperature sensitivity arises from the activation energy associated with voltage-dependent gating 20 . Chimeric and ortholog analyses support a role of the linker region (connecting the N terminus to the pore domain) and the N-terminal domain in thermosensitivity 21,22 . On the other hand, involvement of the outer pore domain in heat sensitivity is supported by mutagenesis and modification of an external cation binding site 23,24 .…”