Cold-sensitive Ion Channel Research Articles

TRPM8 affects relative “cooling and heating” of subcellular organelles in microglia in a context-dependent manner

Thermoregulation and thermal homeostasis at the cellular and subcellular organelle level are poorly understood events. In this work, we used BV2, a microglial cell line, and a series of thermo-sensitive subcellular organelle-specific probes to analyze the relative changes in the spatio-temporal temperatures of different subcellular organelles, both qualitatively and quantitatively. These methodologies allowed us to understand the thermal relationship of different subcellular organelles also. We modulated BV2 cells by pharmacological application of activator or inhibitor of TRPM8 ion channel (a cold-sensitive ion channel) and/or by treating the cells with LPS, a molecule that induces pathogen-associated molecular patterns (PAMPs) signaling. We demonstrate that the temperatures of individual organelles remain variable within a physiological range, yet vary in different conditions. We also demonstrate that treating BV2 cells by TRPM8 modulators and/or LPS alters the organelle temperatures in a specific and context-dependent manner. We show that TRPM8 modulation and/or LPS can alter the relationship of mitochondrial membrane potential to mitochondrial temperature. Our work suggests that mitochondrial temperature positively influences ER temperature and negatively influences Golgi temperature. Golgi temperature positively influences membrane temperature. This understanding of thermal relationships may be crucial for dissecting cellular structures, function, and stress signaling and may be relevant for different diseases.

Hypothalamic TRPM8 and TRPA1 ion channel genes in the regulation of temperature homeostasis at water balance changes

The role of the hypothalamic cold-sensitive ion channels - transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) in homeostatic systems of thermoregulation and water-salt balance – is not clear. The interaction of homeostatic systems of thermoregulation and water-salt balance without additional temperature load did not receive due attention, too. On the models of water-balance disturbance, we tried to elucidate some aspect of these problems.Body temperature (Tbody), O2 consumption, CO2 excretion, electrical muscle activity (EMA), temperature of tail skin (Ttail), plasma osmolality, as well as gene expression of hypothalamic TRPM8 and TRPA1 have been registered in rats of 3 groups: control; water-deprived (3 days under dry–eating); and hyperhydrated (6 days without dry food, drinking liquid 4 % sucrose). No relationship was observed between plasma osmolality and gene expression of Trpm8 and Trpa1. In water-deprived rats, the constriction of skin vessels, increased fat metabolism by 10 % and increased EMA by 48 % allowed the animals to maintain Tbody unchanged. The hyperhydrated rats did not develop sufficient mechanisms, and their Tbody decreased by 0.8 °C. The development of reactions was correlated with the expression of genes of thermosensitive ion channels in the anterior hypothalamus. Ttail had a direct correlation with the expression of the Trpm8 gene, whereas EMA directly correlated with the expression of the Trpa1 gene in water-deprived group. The obtained data attract attention from the point of view of management and correction of physiological functions by modulating the ion channel gene expression.

Research progress on the role of cold-sensitive channel TRPM8 in controlling low temperature-induced bone metabolic imbalance

Abstract With increasing aging population, osteoporosis has emerged as a public health problem worldwide. Epidemiological data reveal that the prevalence of osteoporosis in cold regions is high, and low temperatures may crucially affect bone mass. Recent studies have found that the transient receptor potential melastatin-8 (TRPM8) channel, a cold-sensitive ion channel, can sense cold environment, and can be activated in cold environment. It may play an antagonistic role in low temperature-induced bone mass reduction. Mechanistically, this function may be ascribed to the activation of TRPM8 channel proteins in human bone marrow mesenchymal stem cells (hBM-MSCs), which causes osteoblast differentiation and mineralization in the bone. TRPM8 channel on the surface of brown adipocytes participates in the thermogenesis in brown adipose tissue (BAT) and the regulation of whole-body energy balance to maintain bone homeostasis. TRPM8 may be involved in bone remodeling throughout life. This paper reviews recent research on the possible antagonistic mechanism of TRPM8 in signaling pathways related to low temperature-induced bone mass loss and assesses the possibility of TRPM8 as a molecular target for the prevention and treatment of low temperature-induced osteoporosis in cold regions.

Both heat-sensitive TRPV4 and cold-sensitive TRPM8 ion channels regulate microglial activity

Microglia, the brain-resident macrophages, perform a myriad of functions directed towards development of neural circuits, and their maintenance. A plethora of ion channels aid in microglial activities that are critical for overall brain functioning. Notably, different functions of microglial cells are sensitive to minute temperature changes, as well as mechanical forces. Therefore, among all the players involved in the regulation of microglial functions, thermosensitive TRP ion channels are potentially important. In this study, we report the endogenous and functional presence of a heat-sensitive ion channel TRPV4 and a cold-sensitive ion channel TRPM8 in primary rat microglia and microglial cell line, N9. We demonstrate that pharmacological modulations of both these channels affect intracellular Ca2+-levels, cellular morphology, migration, and motility. Thus, TRPV4 and TRPM8 act as potential regulators of microglial activities. These findings may have broad implications in understanding neuro-glia interactions in neurodevelopmental and neurodegenerative pathologies with overall bio-medical applications.

Effects of activation of skin ion channels TRPM8, TRPV1, and TRPA1 on the immune response. Comparison with effects of cold and heat exposure.

The effects of pharmacological stimulation of skin ion channels TRPA1, TRPM8, TRPV1 on the immune response are presented. These effects are compared with the effects of different types of temperature exposures - skin cooling, deep cooling, and deep heating. This analysis allows us to clear the differences in the influence on the immune response of thermosensitive ion channels localized in the skin; (2) whether the changes in the immune response under temperature exposures are due to these thermosensitive ion channels. Experiments were performed on Wistar rats. For stimulation of TRPM8 ion channel, an application to the skin of 1% menthol was used, for TRPA1 - 0.04% allylisotiocianate, and for TRPV1 - capsaicin in a concentration of 0.001.The antigen binding in the spleen was two-times stimulated by activation of the cold-sensitive ion channel TRPM8 and much weaker by activation of warm-sensitive TRPV1 (by 15%), and another cold-sensitive ion channel TRPA1 (by 40%). Only the stimulation of TRPA1 significantly (by 140%) increased antibody formation in the spleen, while TRPM8 had practically no effect on this process, and activation of TRPV1 significantly (by 60%) inhibited antibody formation. Stimulation of the TRPM8 ion channel significantly (by 60%) reduced the level of IgG in the blood, which is believed to control of infectious diseases.The obtained results show that pharmacological activation of the skin TRPA1, TRPM8, TRPV1 ion channels can differently affect the immune system. At the epicenter of changes there were the antigen binding and antibody formation in the spleen, as well as the level of IgG in the blood. Exactly stimulation of the TRPM8 ion channel determines the changes in the immune response when only the skin is cooling, while at deep body heating, the changes in the immune response are mostly determined by the activation of the skin TRPV1 ion channel.

The Role of Cold-Sensitive Ion Channels in Peripheral Thermosensation.

The detection of ambient cold is critical for mammals, who use this information to avoid tissue damage by cold and to maintain stable body temperature. The transduction of information about the environmental cold is mediated by cold-sensitive ion channels expressed in peripheral sensory nerve endings in the skin. Most transduction mechanisms for detecting temperature changes identified to date depend on transient receptor potential (TRP) ion channels. Mild cooling is detected by the menthol-sensitive TRPM8 ion channel, but how painful cold is detected remains unclear. The TRPA1 ion channel, which is activated by cold in expression systems, seemed to provide an answer to this question, but whether TRPA1 is activated by cold in neurons and contributes to the sensation of cold pain continues to be a matter of debate. Recent advances have been made in this area of investigation with the identification of several potential cold-sensitive ion channels in thermosensory neurons, including two-pore domain potassium channels (K2P), GluK2 glutamate receptors, and CNGA3 cyclic nucleotide-gated ion channels. This mini-review gives a brief overview of the way by which ion channels contribute to cold sensation, discusses the controversy around the cold-sensitivity of TRPA1, and provides an assessment of some recently-proposed novel cold-transduction mechanisms. Evidence for another unidentified cold-transduction mechanism is also presented.

(205) Cellular Mechanisms Underlying Keratinocyte Cold Responses and Subsequent Modulation of Sensory Neuron Thermal Activity

Thermosensation is a critical process through which organisms detect temperature changes within the body and local environment. Convention proposes that thermosensation, and general somatosensation, is mediated exclusively by sensory neurons. Recent publications challenge this idea by describing the role that epidermal cells play in the detection and transmission of mechanical stimuli. Keratinocytes, which constitute 95% of the cells in the epidermis, are depolarized upon mechanical stimulation and release ATP which then modulates sensory neuron responses to mechanical stimuli via P2X4 receptors (Moehring, eLife, 2018). The ability of keratinocytes to respond to cold temperature, another omnipresent sensation, remains unknown. To answer this question, archaerhodopsin-3, an inhibitory opsin, was expressed in epidermal cells. Optogenetic inhibition of epidermal cells significantly decreased cold sensitivity in naive mice; paw withdrawal latencies to a dry ice stimulus were increased by ∼35%. To dissect the keratinocyte signaling pathways mediating the response to cold, calcium imaging was employed. Primary keratinocytes from mouse glabrous skin exhibited rapid and robust responses to a ramp of decreasing bath temperature; of 600+ cells tested, 100% were sensitive to cold stimulation. Cold responses were abolished when extracellular calcium or sodium were omitted from buffer. To specifically assess which cold-sensitive ion channels initiate and sustain this response, various pharmacological agents were included in the cold bath. Finally, the relevance of keratinocyte ATP to sensory neuron P2X4 signaling was assessed with regards to cold sensation. Local hydrolysis of ATP increased paw withdrawal latencies to cold stimuli similar to optogenetic inhibition of keratinocytes. Cell sniff assays confirmed the ability of keratinocytes to release ATP upon cold stimulation. P2X4 sensory neuron knockout mice were also significantly less sensitive to plantar cold stimulation. Collectively, these experiments illustrate the previously unknown ability of keratinocytes to respond to cold and alter downstream sensory neuron responses to cold stimuli.

Phosphoinositide-interacting regulator of TRP (PIRT) has opposing effects on human and mouse TRPM8 ion channels

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensitive ion channel with diverse physiological roles. TRPM8 activity is modulated by many mechanisms, including an interaction with the small membrane protein phosphoinositide-interacting regulator of TRP (PIRT). Here, using comparative electrophysiology experiments, we identified species-dependent differences between the human and mouse TRPM8-PIRT complexes. We found that human PIRT attenuated human TPRM8 conductance, unlike mouse PIRT, which enhanced mouse TRPM8 conductance. Quantitative Western blot analysis demonstrates that this effect does not arise from decreased trafficking of TRPM8 to the plasma membrane. Chimeric human/mouse TRPM8 channels were generated to probe the molecular basis of the PIRT modulation, and the effect was recapitulated in a pore domain chimera, demonstrating the importance of this region for PIRT-mediated regulation of TRPM8. Moreover, recombinantly expressed and purified human TRPM8 S1-S4 domain (comprising transmembrane helices S1-S4, also known as the sensing domain, ligand-sensing domain, or voltage sensing-like domain) and full-length human PIRT were used to investigate binding between the proteins. NMR experiments, supported by a pulldown assay, indicated that PIRT binds directly and specifically to the TRPM8 S1-S4 domain. Binding became saturated as the S1-S4:PIRT mole ratio approached 1. Our results have uncovered species-specific TRPM8 modulation by PIRT. They provide evidence for a direct interaction between PIRT and the TRPM8 S1-S4 domain with a 1:1 binding stoichiometry, suggesting that a functional tetrameric TRPM8 channel has four PIRT-binding sites.

Evaluation of mesenchymal stem cell modulation of trigeminal neuronal responses to cold

Tissue engineering protocols, such as regenerative endodontic procedures (REPs), comprise biologically based procedures designed to restore normal physiologic function. For REPs, the goal is reconstitution of the pulp-dentin complex by delivering mesenchymal stem cells (MSCs), including the stem cells of the apical papilla (SCAP) into a root canal system. Many patients regain cold sensitivity after REPs, but the mechanism is not understood. We hypothesized that SCAP modulate nociceptive function through a paracrine mechanism that activates cold-sensitive ion channels in neurons. We established a co-culture system with human SCAP and rat trigeminal (TG) sensory neurons in order to determine the effect of SCAP co-culture on neuronal responses using whole-cell patch-clamp electrophysiology. TG neurons co-cultured with SCAP demonstrated increased TRPA1-mediated (p<0.01) and TRPM8-mediated inward current densities (p<0.01) at 24h in co-culture. Cold stimulation to SCAP significantly increased ATP release (p<0.01), and supernatant collected after cold stimulation to SCAP was able to activate cultured TG neurons. Co-culture with SCAP significantly increased sustained ATP-evoked inward current density (p<0.05). These data suggest that SCAP release trophic factors that act on afferent neurons to enhance cold-sensitive ion channel activity.

Nutmeg compound is cooler than menthol

Rinsing with menthol-flavored mouthwash causes a tingly, cooling sensation because the compound triggers a cold-sensitive ion channel in sensory neurons. Now scientists have found a compound that is even more chilling. Isolated from nutmeg, the chemical is the most potent activator of the cooling channel yet found in nature (ACS Med. Chem. Lett. 2017, DOI: 10.1021/acsmedchemlett.7b00104). l-Menthol, which comes from mint, is the king of naturally derived cooling compounds and is added to products such as cough drops and cosmetics. But menthol has some shortcomings: At low concentrations, its effect can be weak and short-lived, and bumping up its concentrations too high can cause irritation. To find other cooling agents from natural sources, Tomohiro Shirai and colleagues at Kao Corp. screened extracts of various botanicals and spices for the ability to activate the cold-sensitive ion channel, called transient receptor potential melastatin 8 (TRPM8). After many years of searching, the researchers

Cold-sensitive ion channels are involved in chilling injury of pig oocytes

Cold-sensitive ion channels are involved in chilling injury of pig oocytes

The influence of cooling and TRPM8 ion channel activation on the level of pro-inflammatory cytokines in normotensive and hypertensive rats

The role of thermosensitive TRP ion channels in physiological processes in the whole organism is far from being clear. In present work we tried to understand the possible participation of the cold-sensitive ion channel TRPM8 in regulation of the pro-inflammatory cytokine level in blood, and to see if hypertension (widely spread disease) changes this relationship. Experiments were carried out on normotensive Wistar rats and rats with inherited stress-induced arterial hypertension. The effects of deep rapid and slow cooling with decrease in rectal temperature by 3°C, and activation of the skin TRPM8 ion channel by its agonist menthol (application of 1% L-menthol) on the concentration of pro-inflammatory cytokines (IL-6, IL-1β and TNFα) in blood have been studied. The data have shown that the TRPM8 ion channel participates in regulation of pro-inflammatory cytokine in the whole organism, as well as exposure to cold. In normotensive animals the activation of the cold-sensitive TRPM8 ion channel in skin by its agonist menthol without any temperature shifts causes an increase (about two fold) of pro-inflammatory cytokines IL-6 and IL-1 β in blood without any changes in the level of TNFα. The effect of cooling (slow or rapid) on IL-6 and IL-1β is comparable with the effect of the TRPM8 activation. The changes in TNFα concentration were observed only at slow cooling. In hypertensive rats there were no changes in the level of pro-inflammatory cytokines under the effect of cooling or activation of the TRPM8 ion channel. This evidences for the decrease in TRPM8 activity under arterial hypertension. One of possible mechanisms of profound changes at arterial hypertension may be the alteration in activity of some ion channels, and TRPM8 is one of them.

Chapter Eleven - Intimacies and Physiological Role of the Polymodal Cold-Sensitive Ion Channel TRPM8

The detection of environmental temperature is critical for the survival of the most diverse organisms. Thermosensitive transient receptor potential (thermoTRP) channels have evolved as a class of ion channels activated by a wide range of temperatures. These molecular thermal sensors are spread through the different TRP channel subfamilies. Among the Melastatin subfamily of TRP channels, the eighth member, TRPM8, is a calcium-permeable cationic ion channel activated by cold, by substances that evoke cold sensation such as menthol, and by voltage. This channel is considered the main molecular entity responsible for the sensitivity to cold of primary sensory neurons of the somatosensory system. Here we present to the readers a summary of some the most relevant biophysical properties, physiological role, and molecular intimacies of this polymodal thermoTRP channel.

A Large-Scale Behavioral Screen to Identify Neurons Controlling Motor Programs in the Drosophila Brain

Drosophila is increasingly used for understanding the neural basis of behavior through genetically targeted manipulation of specific neurons. The primary approach in this regard has relied on the suppression of neuronal activity. Here, we report the results of a novel approach to find and characterize neural circuits by expressing neuronal activators to stimulate subsets of neurons to induce behavior. Classical electrophysiological studies demonstrated that stimulation of command neurons could activate neural circuits to trigger fixed action patterns. Our method was designed to find such command neurons for diverse behaviors by screening flies in which random subsets of brain cells were activated. We took advantage of the large collection of Gal4 lines from the NP project and crossed 835 Gal4 strains with relatively limited Gal4 expression in the brain to flies carrying a UAS transgene encoding TRPM8, a cold-sensitive ion channel. Low temperatures opened the TRPM8 channel in Gal4-expressing cells, leading to their excitation, and in many cases induced overt behavioral changes in adult flies. Paralysis was reproducibly observed in the progeny of crosses with 84 lines, whereas more specific behaviors were induced with 24 other lines. Stimulation performed using the heat-activated channel, TrpA1, resulted in clearer and more robust behaviors, including flight, feeding, and egg-laying. Through follow-up studies starting from this screen, we expect to find key components of the neural circuits underlying specific behaviors, thus providing a new avenue for their functional analysis.

Effects of Pharmacological Activation of TRPM8 Ion Channels on the Thermoregulatory Responses during Warming

Preliminary non-thermal activation of cold-sensitive TRPM8 ion channel facilitates initiation of the heat-defense responses in homoiothermal animals by decreasing temperature threshold of the vasodilatory response. TRPM8 activation leads to earlier heat-initiated increase in oxygen consumption, but reduces its magnitude. Warming inhibits the lipolytic effect of menthol activation of TRPM8 observed under thermoneutral conditions. Thus, modulation of the skin temperature afferent signal by ion channel agonist TRPM8 changes not only cold-defense, but also heat-defense responses of the body.

Differential inhibition of the TRPM8 ion channel by Gαq and Gα11

Cold temperature is encoded by the cold-sensitive ion channel TRPM8 in somatosensory neurons. It has been unclear how TRPM8 is modulated so that it can mediate distinct type of cold signaling. We have recently reported that activated Gαq directly inhibits TRPM8 after activation of Gq-coupled receptors. Here, we further show that activation of the muscarinic receptor M1R, which is known to inhibit M currents through PLCβ-mediated hydrolysis of PtdIns(4,5)P2, similarly inhibited TRPM8 potently, but inhibition was not prevented by the PLC inhibitor U73122. Interestingly, although Gαq and Gα11 are indistinguishable in activating PLCβ and hydrolysing PtdIns(4,5)P2, activated Gα11 inhibited TRPM8 to a lesser extent than activated Gαq. The differential TRPM8 inhibition is determined by a specific residue E197 on Gα11, because mutating this residue to the corresponding residue on Gαq restored TRPM8 inhibition to a similar degree as mediated by Gαq. These results reinforce the idea that activated Gαq directly inhibits TRPM8 independently from PtdIns(4,5)P2 hydrolysis-mediated inhibition of TRPM8.

Participation of cold sensitive TRPM8 ion channel in modulation of metabolism and immune response

Event Abstract Back to Event Participation of cold sensitive TRPM8 ion channel in modulation of metabolism and immune response Tamara V. Kozyreva1* 1 Institute of Physiology Russian Academy of Medical Sciences, Thermophysiology, Russia The response of living organism to any stimulus is a combination of the responses of various physiological systems which is determined by the regulatory afferent structures providing constant and precise interaction of the systems. Relationship of thermoregulatory and immune systems is an important aspect of unsolved problems, because the widespread influence of temperature on the body. Results of recent studies indicate that temperature-sensitive TRP ion channels are the basis of thermoreceptors which form the response to temperature. Cold-sensitive ion channel TRPM8 is most interesting because it works in the range of physiological temperatures. One of the TRPM8 agonists is menthol. Currently, more attention is attracted to physiological and pathological functions of TRP ion channels but their possible role in maintenance of body health is not clear. In thermoneutral conditions (Fig. 1, top) activation of the cold-sensitive TRPM8 ion channel by menthol, produces a significant increase in total metabolism due to enhancement of fat oxidation. The observed shift in metabolism without any temperature changes but under the effect of TRPM8 activation suggests its continuous involvement in regulation of total metabolism and, presumably, in defining the particular type of metabolism of living organism (Kozyreva et al., 2010). Activation of TRPM8 in thermoneutral conditions causes also changes in immune response: 1) significant increase in antigen binding in spleen and peritoneal exudate; 2) suppression of antibody formation in spleen; 3) considerable decrease in blood level of IgG (Kozyreva et al., 2012). The measurement of the blood level of interleukins (Kits ELISA) has shown that activation of TRPM8 ion channel by menthol increases the level of IL-6 and IL-1β (Fig. 2). This was quit close to changes in these cytokine levels at slow deep cooling. This allows us to suggest the participation of TRPM8 ion channel in regulation of these cytokine levels. At cooling (Fig. 1, bottom). Agonist of cold-sensitive TRPM8 ion channel, menthol decreases the temperature thresholds of all thermoregulatory responses to cooling (heat production and heat loss). Under menthol stimulation, there was enhancement of the urgent phase of metabolic response at rapid cooling, and an increase in the skin blood vessel constrictor response at slow cooling. We have shown that shallow cooling stimulates but deep cooling inhibits the immune response. Activation of TRPM8 ion channel by menthol eliminates the inhibitory effect of subsequent deep cooling on immune response (Kozyreva et al., 2002; 2010; 2012). Thus, activation of TRPM8 by menthol enhances the resistance of organism to cooling by better maintenance of both temperature homeostasis and the function of immune system. It can be suggested that a significant influence of TRPM8 agonist menthol on the immune response is mainly related to its peripheral effects. This is in consistent with our data (Voronova et al., 2013) on not high expression of Trpm8 gene in brain structures, and evidenced expression of this ion channel in sensory skin afferents (Dhaka et al., 2008). Elucidation of the mechanisms of TRPM8 ion channel effects requires further researches. Figure 1 Figure 2

Agonist of TRPM8 channel, menthol, facilitates the initiation of thermoregulatory responses to external cooling

The effects of activation of the cold and menthol sensitive TRPM8 ion channel on different thermoregulatory parameters (total oxygen consumption, carbon dioxide release, respiratory coefficient, vasoconstriction response of skin blood vessels and shivering) were studied in anaesthetized rats subjected to two types of external cooling—rapid and slow. Activation of TRPM8 by menthol even in thermoneutral conditions produced an increase in oxygen consumption and decrease in respiratory coefficient, which may be evidence of enhanced fat oxidation. Menthol, an agonist of the cold sensitive TRPM8 ion channel, decreased the temperature thresholds of all thermoregulatory responses induced by rapid and slow cooling without affecting the sequence of their initiation. Under menthol stimulation, there was enhancement of the first (urgent) phase of metabolic response at rapid cooling, and an increase in the skin blood vessel constrictor response at slow cooling. These changes lead to improved maintenance of core temperature when the organism is subjected to rapid or slow cooling. These data are compelling evidence for the contribution of TRPM8 ion channels to the formation of the thermal afferent signals in the initiation of cold defense responses. The effects of TRPM8 activation by menthol on metabolic parameters in thermoneutral conditions and under cooling suggest the continuous involvement of TRPM8 channel in regulation of total metabolism.

Molecular and Cellular Mechanisms of Trigeminal Chemosensation

Three sensory systems, olfaction, taste, and somatosensation, are dedicated to the detection of chemicals in the environment. Trigeminal somatosensory neurons enable us to detect a wide range of environmental stimuli, including pressure, temperature, and chemical irritants, within the oral and nasal mucosa. Natural plant-derived irritants have served as powerful pharmacological tools for identifying receptors underlying somatosensation. This is illustrated by the use of capsaicin, menthol, and wasabi to identify the heat-sensitive ion channel TRPV1, the cold-sensitive ion channel TRPM8, and the irritant receptor TRPA1, respectively. In addition to TRP channels, members of the two-pore potassium channel family have also been implicated in trigeminal chemosensation. KCNK18 was recently identified as a target for hydroxy-alpha-sanshool, the tingling and numbing compound produced in Schezuan peppers and other members of the Xanthoxylum genus. The role of these channels in trigeminal thermosensation and pain will be discussed.

Evolution of Thermal Response Properties in a Cold-Activated TRP Channel

Animals sense changes in ambient temperature irrespective of whether core body temperature is internally maintained (homeotherms) or subject to environmental variation (poikilotherms). Here we show that a cold-sensitive ion channel, TRPM8, displays dramatically different thermal activation ranges in frogs versus mammals or birds, consistent with variations in these species' cutaneous and core body temperatures. Thus, somatosensory receptors are not static through evolution, but show functional diversity reflecting the characteristics of an organism's ecological niche.