Thermosensitive Transient Receptor Potential Research Articles

Role of Thermo-Sensitive Transient Receptor Potential Channels in Brown Adipose Tissue.

Brown and beige adipocytes are a major site of mammalian non-shivering thermogenesis and energy dissipation. Obesity is caused by an imbalance between energy intake and expenditure and has become a worldwide health problem. Therefore modulation of thermogenesis in brown and beige adipocytes could be an important application for body weight control and obesity prevention. Over the last few decades, the involvement of thermo-sensitive transient receptor potential (TRP) channels (including TRPV1, TRPV2, TRPV3, TRPV4, TRPM4, TRPM8, TRPC5, and TRPA1) in energy metabolism and adipogenesis in adipocytes has been extensively explored. In this review, we summarize the expression, function, and pathological/physiological contributions of these TRP channels and discuss their potential as future therapeutic targets for preventing and combating human obesity and obesity-related metabolic disorders.

Mammalian cold TRP channels: impact on thermoregulation and energy homeostasis.

Body temperature regulation is a fundamental homeostatic function in homeothermic animals. It is governed by the central nervous system that integrates temperature signals from internal body structures and the skin and provides efferent responses to adjust heat-exchange rates with the environment. Thermoregulation has a major influence on energy balance by regulating food intake as well as heat production and energy expenditure. Surprisingly, although almost 50% of our energy expenditure is dedicated to maintaining homeothermy, very little is yet known about the molecular aspects and the neural wiring involved in the intimate interrelationship between these two critical homeostatic systems. Some non-selective cation channels of the transient receptor potential (TRP) family work as molecular thermal sensors in sensory neurons and other cells. In this review, we discuss recent advances in our understanding of the basic mechanisms responsible for thermoregulation in the cold. We have focused our attention on the role of two cold-activated TRP channels (transient receptor potential melastatin 8 and transient receptor potential ankyrin 1) in body temperature regulation as well as their impact on energy balance and metabolism. A better understanding of the mechanisms coupling thermoregulation to energy homeostasis, including the involvement of thermosensitive TRPs, may uncover additional mechanisms underlying the pathogenesis of obesity and its metabolic consequences in humans, opening new strategies for the diagnosis, treatment, and prevention of this disease.

TRPV4 heats up ANO1-dependent exocrine gland fluid secretion.

Several ion channels and transporters regulate fluid secretion in salivary and lacrimal glands. In salivary glands, the major anion channel involved in fluid secretion is the calcium-activated chloride channel anoctamin 1 (ANO1). Several members of the transient receptor potential (TRP) channel superfamily regulate ANO1 activity. Here, we report a functional interaction between thermosensitive TRP vanilloid (TRPV)4 and ANO1 in acinar cells isolated from mouse salivary and lacrimal glands. TRPV4 activation induced chloride currents and shrinkage of acinar cells by increasing intracellular calcium concentrations. The chloride currents evoked by a TRPV4-specific activator (GSK1016790A) were identified as ANO1-mediated currents. Moreover, TRPV4 activation by an inositol 1,4,5-trisphosphate (IP3)-dependent mechanism was found to contribute to the muscarinic pathway of fluid secretion. Muscarinic stimulation of saliva and tear secretion was down-regulated in both TRPV4-deficient mice and in acinar cells treated with a TRPV4-specific antagonist (HC-067047). Furthermore, the temperature dependence of muscarinic salivation was shown to depend mainly on TRPV4. Our results suggest that TRPV4 interacts with IP3 receptors and ANO1 to regulate the muscarinic pathway that mediates salivation and lacrimation.-Derouiche, S., Takayama, Y., Murakami, M., Tominaga, M. TRPV4 heats up ANO1-dependent exocrine gland fluid secretion.

Modulation of Itch by Localized Skin Warming and Cooling.

Skin thermal changes modulate itch sensitivity. However, the mechanisms of this modulation are still unclear. Using mouse models of acute and chronic itch, we investigated whether local innocuous thermal stimulation of the skin alters itch sensitivity and if blockade of thermosensitive transient receptor potential (TRP) channels can reduce these changes. Localized thermal changes were achieved by placing a thermal probe in contact with the back skin for 30 s. Warming the skin significantly increased serotonin-evoked scratching and spontaneous scratching in the ovalbumin model of atopic dermatitis but decreased histamine-evoked scratching. These changes were blocked by a TRPV4 antagonist. Cooling the skin significantly increased serotonin-evoked scratching but reduced histamine-evoked scratching. The increase in serotonin-evoked scratching, but not the reduction of histamine-evoked scratching, was blocked by TRPM8 antagonism. Chloroquine-evoked scratching was unaffected by either warming or cooling. Our data indicate that different itch signaling pathways are differentially modulated by skin thermal changes.

Thermo-Sensitive TRP Channels: Novel Targets for Treating Chemotherapy-Induced Peripheral Pain.

Abnormal Ca2+ channel physiology, expression levels, and hypersensitivity to heat have been implicated in several pain states following treatment with chemotherapeutic agents. As members of the Ca2+ permeable transient receptor potential (TRP), five of the channels (TRPV1-4 and TRPM2) are activated by different heat temperatures, and two of the channels (TRPA1 and TRPM8) are activated by cold temperature. Accumulating evidences indicates that antagonists of TRPA1 and TRPM8 may protect against cisplatin, oxaliplatin, and paclitaxel-induced mitochondrial oxidative stress, inflammation, cold allodynia, and hyperalgesia. TRPV1 was responsible from the cisplatin-induced heat hyperalgesia and mechanical allodynia in the sensory neurons. TRPA1, TRPM8, and TRPV2 protein expression levels were mostly increased in the dorsal root (DRG) and trigeminal ganglia by these treatments. There is a debate on direct or oxaliplatin-induced oxidative cold stress dependent TRPA1 and TRPV4 activation in the DRG. Involvement of molecular pathways such as cysteine groups, glutathione metabolism, anandamide, cAMP, lipopolysaccharide, proteinase-activated receptor 2, and mitogen-activated protein kinase were also indicated in the oxaliplatin and paclitaxel-induced cold allodynia. In this review, we summarized results of five temperature-regulated TRP channels (TRPA1, TRPM8, TRPV1, TRPV2, and TRPV4) as novel targets for treating chemotherapy-induced peripheral pain

The Drosophila TRPA1 Channel and Neuronal Circuits Controlling Rhythmic Behaviours and Sleep in Response to Environmental Temperature.

trpA1 encodes a thermosensitive transient receptor potential channel (TRP channel) that functions in selection of preferred temperatures and noxious heat avoidance. In this review, we discuss the evidence for a role of TRPA1 in the control of rhythmic behaviours in Drosophila melanogaster. Activity levels during the afternoon and rhythmic temperature preference are both regulated by TRPA1. In contrast, TRPA1 is dispensable for temperature synchronisation of circadian clocks. We discuss the neuronal basis of TRPA1-mediated temperature effects on rhythmic behaviours, and conclude that they are mediated by partly overlapping but distinct neuronal circuits. We have previously shown that TRPA1 is required to maintain siesta sleep under warm temperature cycles. Here, we present new data investigating the neuronal circuit responsible for this regulation. First, we discuss the difficulties that remain in identifying the responsible neurons. Second, we discuss the role of clock neurons (s-LNv/DN1 network) in temperature-driven regulation of siesta sleep, and highlight the role of TRPA1 therein. Finally, we discuss the sexual dimorphic nature of siesta sleep and propose that the s-LNv/DN1 clock network could play a role in the integration of environmental information, mating status and other internal drives, to appropriately drive adaptive sleep/wake behaviour.

Temperature Impacts on Transient Receptor Potential Channel Mediated Calcium Oscillations in Astrocytes**Supported by the National Natural Science Foundation of China under Grant Nos 11175055 and 11547013, and the Natural Science Foundation of Hebei Province under Grant No A2015202268.

We computationally study the possible effects of thermosensitive transient receptor potential (TRP) channels on the spontaneous calcium oscillations in astrocytes at various temperatures. Based on the previous model and the result of thermosensitive TRP channels’ open probabilities, some meaningful conclusions are obtained. It is shown that the occurrence of calcium oscillations depends on temperature and the molar heat capacity difference between the closed and open channels (). The data indicate that calcium oscillations in astrocytes occurred in the ranges of 7 °C–11 °C and 27 °C–30 °C when is , and calcium oscillations only occur in the range of 27 °C–30 °C when is . In this study, the frequency decreases rapidly at temperatures ranging from 7 °C to 11 °C, and there is a contrary result in the range of 27 °C–30 °C.

Involvement of thermosensitive TRP channels in energy metabolism.

To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.

Gene expression changes of thermo-sensitive transient receptor potential channels in obese mice.

Adipose tissues play key roles in energy homeostasis. Brown adipocytes and beige adipocytes in white adipose tissue (WAT) share the similar characters of thermogenesis, both of them could be potential targets for obesity management. Several thermo-sensitive transient receptor potential channels (thermoTRPs) are shown to be involved in adipocyte biology. However, the expression pattern of thermoTRPs in adipose tissues from obese mice is still unknown. The mRNA expression of thermoTRPs in subcutaneous WAT (sWAT) and interscapular brown adipose tissue (iBAT) from lean and obese mice were measured using reverse transcriptase-quantitative PCRs (RT-qPCR). The results demonstrated that all 10 thermoTRPs are expressed in both iBAT and sWAT, and without significant difference in the mRNA expression level of thermoTRPs between these two tissues. Moreover, Trpv1 and Trpv3 mRNA expression levels in both iBAT and sWAT were significantly decreased in high fat diet (HFD)-induced obese mice and db/db (leptin receptor deficient) mice. Trpm2 mRNA expression level was significantly decreased only in sWAT from HFD-induced obese mice and db/db mice. On the other hand, Trpv2 and Trpv4 mRNA expression levels in iBAT and sWAT were significantly increased in HFD-induced obese mice and db/db mice. Taken together, we conclude that all 10 thermoTRPs are expressed in iBAT and sWAT. And several thermoTRPs differentially expressed in adipose tissues from HFD-induced obese mice and db/db mice, suggesting a potential involvement in anti-obesity regulations.

Thermogenetic neurostimulation with single-cell resolution

Thermogenetics is a promising innovative neurostimulation technique, which enables robust activation of neurons using thermosensitive transient receptor potential (TRP) cation channels. Broader application of this approach in neuroscience is, however, hindered by a limited variety of suitable ion channels, and by low spatial and temporal resolution of neuronal activation when TRP channels are activated by ambient temperature variations or chemical agonists. Here, we demonstrate rapid, robust and reproducible repeated activation of snake TRPA1 channels heterologously expressed in non-neuronal cells, mouse neurons and zebrafish neurons in vivo by infrared (IR) laser radiation. A fibre-optic probe that integrates a nitrogen−vacancy (NV) diamond quantum sensor with optical and microwave waveguide delivery enables thermometry with single-cell resolution, allowing neurons to be activated by exceptionally mild heating, thus preventing the damaging effects of excessive heat. The neuronal responses to the activation by IR laser radiation are fully characterized using Ca2+ imaging and electrophysiology, providing, for the first time, a complete framework for a thermogenetic manipulation of individual neurons using IR light.

Possible contribution of pannexin-1 to capsaicin-induced ATP release in rat nasal columnar epithelial cells

ABSTRACTCurrent evidence indicates that transient receptor potential (TRP) channel activity involves a relationship between opening of pannexin-1 and release of ATP into the extracellular space. We examined the effects of agonists of thermosensitive TRP channels (TRPM8, TRPA1, TRPV1, and TRPV2) on ATP release from rat nasal mucosa, and measured ciliary beat frequency (CBF) using digital high-speed video imaging. Single-cell patch clamping from dissociated rat nasal columnar epithelial cells was performed to confirm the relationship between pannexin-1 and TRP. We demonstrated that ATP release and CBF were significantly potentiated by the heat-sensitive TRPV1 agonist capsaicin (10 μM), but not by other TRP agonists. Capsaicin-induced ATP release and CBF increase were significantly inhibited by the pannexin-1 blockers carbenoxolone (10 μM) and probenecid (300 μM). In addition, the voltage step-evoked currents in the presence of capsaicin were inhibited by the pannexin-1 blockers in single-cell patch clamping. Our results suggest the participation of TRPV1 and pannexin-1 in the physiologic functions of rat nasal mucosa.

Side chain flexibility and coupling between the S4-S5 linker and the TRP domain in thermo-sensitive TRP channels: Insights from protein modeling.

The transient receptor potential (TRP) superfamily is subdivided into several subfamilies on the basis of sequence similarity, which is highly heterogeneous but shows a molecular architecture that resembles the one present in members of the Kv channel superfamily. Because of this diversity, they produce a large variety of channels with different gating and permeability properties. Elucidation of these particular features necessarily requires comparative studies based on structural and functional data. The present study aims to compilate, analyze, and determine, in a coherent way, the relationship between intrinsic side-chain flexibility and the allosteric coupling in members of the TRPV, TRPM, and TRPC families. Based on the recently determined structures of TRPV1 and TRPV2, we have generated protein models for single subunits of TRPV5, TRPM8, and TRPC5 channels. With these models, we focused our attention on the apparently crucial role of the GP dipeptide at the center of the S4-S5 linker and discussed its role in the interaction with the TRP domain, specifically with the highly-conserved Trp during this coupling. Our analysis suggests an important role of the S4-S5L flexibility in the thermosensitivity, where heat-activated channels possess rigid S4-S5 linkers, whereas cold-activated channels have flexible ones. Finally, we also present evidence of the key interaction between the conserved Trp residue of the TRP box and of several residues in the S4-S5L, importantly the central Pro. Proteins 2017; 85:630-646. © 2016 Wiley Periodicals, Inc.

Heat induces interleukin-6 in skeletal muscle cells via TRPV1/PKC/CREB pathways.

Interleukin-6 (IL-6) is released from skeletal muscle cells and induced by exercise, heat, catecholamine, glucose, lipopolysaccharide, reactive oxygen species, and inflammation. However, the mechanism that induces release of IL-6 from skeletal muscle cells remains unknown. Thermosensitive transient receptor potential (TRP) proteins such as TRPV1-4 play vital roles in cellular functions. In this study we hypothesized that TRPV1 senses heat, transmits a signal into the nucleus, and produces IL-6. The purpose of the present study is to investigate the underlying mechanisms whereby skeletal muscle cells sense and respond to heat. When mouse myoblast cells were exposed to 37-42°C for 2 h, mRNA expression of IL-6 increased in a temperature-dependent manner. Heat also increased IL-6 secretion in myoblast cells. A fura 2 fluorescence dual-wavelength excitation method showed that heat increased intracellular calcium flux in a temperature-dependent manner. Intracellular calcium flux and IL-6 mRNA expression were increased by the TRPV1 agonists capsaicin and N-arachidonoyldopamine and decreased by the TRPV1 antagonists AMG9810 and SB366791 and siRNA-mediated knockdown of TRPV1. TRPV2, 3, and 4 agonists did not change intracellular calcium flux. Western blotting with inhibitors demonstrated that heat increased phosphorylation levels of TRPV1, followed by PKC and cAMP response element-binding protein (CREB). PKC inhibitors, Gö6983 and staurosporine, CREB inhibitors, curcumin and naphthol AS-E, and knockdown of CREB suppressed the heat-induced increases in IL-6. These results indicate that heat increases IL-6 in skeletal muscle cells through the TRPV1, PKC, and CREB signal transduction pathway.NEW & NOTEWORTHY Heat increases the release of interleukin-6 (IL-6) from skeletal muscle cells. IL-6 has been shown to serve immune responses and metabolic functions in muscle. It can be anti-inflammatory as well as proinflammatory. However, the mechanism that induces release of IL-6 from skeletal muscle cells remains unknown. Here we show that heat increases IL-6 in skeletal muscle cells through the transient receptor potential vannilloid 1, PKC, and cAMP response element-binding protein signal transduction pathway.

Abstract 12450: Trpv1 Responses to Heat and Induces Il-6 Production in Skeletal Muscle Cells

Introduction: Interluekin-6 (IL-6) is released from skeletal muscle cells and induced by exercise, heat, catecholamine, glucose, lipopolysaccharide, reactive oxygen species, and inflammation. However, the mechanism, which induces release of IL-6 from skeletal muscle cells, remains unknown. Thermo-sensitive transient receptor potential subfamily V member 1 (TRPV1) plays vital roles in cellular functions. Hypothesis: We hypothesized thatTRPV1 senses heat, transmits a signal into the nucleus, and produces IL-6. We investigated the underlying mechanisms, where skeletal muscle cells sense heat and respond to it. Methods: Mouse C2C12 myoblast cells were cultured at 37°C under 5% CO 2 atmosphere. When cells were exposed to heat, culture dishes were placed in another incubator which was preset to an environment temperature of 39°C, 40°C, 41°C, and 42°C. The calcium influx concentration was measured by a fura-2 fluorescence dual-wavelength excitation method. The IL-6 mRNA expression level of IL-6 was analyzed by using real-time PCR. The protein density level of IL-6 released from myoblast cells was analyzed by using an ELISA. The phosphorylation level of TRPV1 was analyzed by using western blotting. Results: When myoblast cells were exposed to temperatures ranging from 37 degrees C to 42 degrees C for two hours, the mRNA expression of IL-6 increased in a temperature-dependent manner. Heat also increased IL-6 secretion. Heat increased the intracellular calcium flux temperature-dependently. TRPV1 agonists, capsaicin and NADA, increased the intracellular calcium flux and the IL-6 mRNA expression, while TRPV1 antagonists, AMG9810 and SB366791, and the siRNA mediated knockdown of TRPV1 decreased them. Western blotting with inhibitors demonstrated that heat increased the phosphorylation levels of TRPV1 followed by PKC and CREB. PKC inhibitors, Go6983 and staurosporine, CREB inhibitors, curcumin and naphthol AS-E, and the knockdown of CREB suppressed the heat induced increases of IL-6 mRNA. Conclusions: TRPV1 senses heat and increases IL-6 production in skeletal muscle cells through the PKC and CREB pathway. Moreover it suggests that hyperthermic conditioning is effective for the exercise therapy or rehabilitation.

Thyronamines and Derivatives: Physiological Relevance, Pharmacological Actions, and Future Research Directions.

Thyronamines (3-T1AM, T0AM) are endogenous compounds probably derived from L-thyroxine or its intermediate metabolites. Combined activities of intestinal deiodinases and ornithine decarboxylase generate 3-T1AM in vitro. Alternatively, 3-T1AM might be formed by the thyroid gland and secreted into the blood. 3-T1AM and T0AM concentrations have been determined by liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) in tissues, serum, and cell lines. However, large variations of 3-T1AM concentrations in human serum were reported by LC-MS/MS compared with a monoclonal antibody-based immunoassay. These differences might be caused by strong binding of the highly hydrophobic 3-T1AM to apolipoprotein B100. Pharmacological administration of 3-T1AM results in dose-dependent reversible effects on body temperature, cardiac function, energy metabolism, and neurological functions. The physiological relevance of these actions is unclear, but may occur at tissue concentrations close to the estimated endogenous concentrations of 3-T1AM or its metabolites T0AM or thyroacetic acid (TA1). A number of putative receptors, binding sites, and cellular target molecules mediating actions of the multi-target ligand 3-T1AM have been proposed. Among those are members of the trace amine associated receptor family, the adrenergic receptor ADRα2a, and the thermosensitive transient receptor potential melastatin 8 channel. Preclinical studies employing various animal experimental models are in progress, and more stable receptor-selective agonistic and antagonistic analogues of 3-T1AM are now available for testing. The potent endogenous thyroid hormone-derived biogenic amine 3-T1AM exerts marked cryogenic, metabolic, cardiac and central actions and represents a valuable lead compound linking endocrine, metabolic, and neuroscience research to advance development of new drugs.

Allosterism and Structure in Thermally Activated Transient Receptor Potential Channels.

The molecular sensors that mediate temperature changes in living organisms are a large family of proteins known as thermosensitive transient receptor potential (TRP) ion channels. These membrane proteins are polymodal receptors that can be activated by cold or hot temperatures, depending on the channel subtype, voltage, and ligands. The stimuli sensors are allosterically coupled to a pore domain, increasing the probability of finding the channel in its ion conductive conformation. In this review we first discuss the allosteric coupling between the temperature and voltage sensor modules and the pore domain, and then discuss the thermodynamic foundations of thermo-TRP channel activation. We provide a structural overview of the molecular determinants of temperature sensing. We also posit an anisotropic thermal diffusion model that may explain the large temperature sensitivity of TRP channels. Additionally, we examine the effect of several ligands on TRP channel function and the evidence regarding their mechanisms of action.

An Introduction to this Special Issue: Animal Models of Human Chemosensory Perception and Behavior

In this Special Issue of Chemosensory Perception, the important link connecting chemosensory work in animals to human perception and behavior is highlighted. Historically, the use of animal models has been instrumental in developing our understanding of the human condition. Tremendous insight and scientific advancement has been made through the development of applicable animal models. In the case of the chemical senses, this has been especially true as animal models have been used to identify the key proteins involved in chemosensory transduction; to investigate the neural code underpinning taste, smell, and chemesthetic sensations; and, more recently, to examine the function of taste and smell receptors in roles other than gustation and olfaction. Linking results from animal and human studies is critically important to the chemical senses discipline. For those scientists whose techniques and interests focus primarily on human perception, a clear understanding of the molecular and physiological phenomena underpinning chemosensation provides a fundamental platform upon which to base further hypotheses. On the other hand, the impact of animal work is greatest when findings are translated to human significance.Moreover, the chemosensory community is unique in that the largest global industry—food, beverage, and consumer products—is a direct beneficiary of the research efforts and can leverage results to improve the quality, healthiness, and acceptance of products in this category. As such, translatable findings help fuel the economic engine of this important industrial sector. In the current Special Issue of Chemosensory Perception, six papers have been authored with the intent to provide human relevance to chemosensory studies completed using animals. The articles represent a small collection of the numerous animal studies that have contributed to our current knowledge, yet provide broad perspective covering topics of interest within chemosensation. Three of the articles focus on the sense of taste and provide evidence that data obtained in rodents are relevant to understanding appetitive taste processing and ingestive behavior, as well as offering key insights related to human issues of obesity and weight management. The fourth article concerns olfaction and posits an interesting role of the lung in retronasal odor perception. The last two articles focus on chemesthesis, particularly the remarkable overlap of trigeminal chemosensitivity obtained from animals and human psychophysical work as well as the role of thermosensitive transient receptor potential (TRP) channels in touch, temperature, and pain sensation. I would like to thank the authors for contributing these papers and acknowledge their time and dedication to preparing these manuscripts. As an advocate of linking human perception and behavior to underlying neurobiological mechanisms, I believe the content of this Special Issue of Chemosensory Perception makes an important contribution to the field of chemosensation. I hope you agree.

Thermosensation and longevity.

Temperature has profound effects on behavior and aging in both poikilotherms and homeotherms. To thrive under the ever fluctuating environmental temperatures, animals have evolved sophisticated mechanisms to sense and adapt to temperature changes. Animals sense temperature through various molecular thermosensors, such as thermosensitive transient receptor potential (TRP) channels expressed in neurons, keratinocytes, and intestine. These evolutionarily conserved thermosensitive TRP channels feature distinct activation thresholds, thereby covering a wide spectrum of ambient temperature. Temperature changes trigger complex thermosensory behaviors. Due to the simplicity of the nervous system in model organisms such as Caenorhabditis elegans and Drosophila, the mechanisms of thermosensory behaviors in these species have been extensively studied at the circuit and molecular levels. While much is known about temperature regulation of behavior, it remains largely unclear how temperature affects aging. Recent studies in C. elegans demonstrate that temperature modulation of longevity is not simply a passive thermodynamic phenomenon as suggested by the rate-of-living theory, but rather a process that is actively regulated by genes, including those encoding thermosensitive TRP channels. In this review, we discuss our current understanding of thermosensation and its role in aging.

Understanding thermosensitive transient receptor potential channels as versatile polymodal cellular sensors.

Transient receptor potential (TRP) ion channels are eukaryotic polymodal sensors that function as molecular cellular signal integrators. TRP family members sense and are modulated by a wide array of inputs, including temperature, pressure, pH, voltage, chemicals, lipids, and other proteins. These inputs induce signal transduction events mediated by nonselective cation passage through TRP channels. In this review, we focus on the thermosensitive TRP channels and highlight the emerging view that these channels play a variety of significant roles in physiology and pathophysiology in addition to sensory biology. We attempt to use this viewpoint as a framework to understand the complexity and controversy of TRP channel modulation and ultimately suggest that the complex functional behavior arises inherently because this class of protein is exquisitely sensitive to many diverse and distinct signal inputs. To illustrate this idea, we primarily focus on TRP channel thermosensing. We also offer a structural, biochemical, biophysical, and computational perspective that may help to bring more coherence and consensus in understanding the function of this important class of proteins.

Thermosensitive transient receptor potential (TRP) channel agonists and their role in mechanical, thermal and nociceptive sensations as assessed using animal models.

The present paper summarizes research using animal models to investigate the roles of thermosensitive transient receptor potential (TRP) channels in somatosensory functions including touch, temperature and pain. We present new data assessing the effects of eugenol and carvacrol, agonists of the warmth-sensitive TRPV3, on thermal, mechanical and pain sensitivity in rats. Thermal sensitivity was assessed using a thermal preference test, which measured the amount of time the animal occupied one of two adjacent thermoelectric plates set at different temperatures. Pain sensitivity was assessed as an increase in latency of hindpaw withdrawal away from a noxious thermal stimulus directed to the plantar hindpaw (Hargreaves test). Mechanical sensitivity was assessed by measuring the force exerted by an electronic von Frey filament pressed against the plantar surface that elicited withdrawal. Topical application of eugenol and carvacrol did not significantly affect thermal preference, although there was a trend toward avoidance of the hotter surface in a 30 vs. 45°C preference test for rats treated with 1 or 10% eugenol and carvacrol. Both eugenol and carvacrol induced a concentration-dependent increase in thermal withdrawal latency (analgesia), with no significant effect on mechanosensitivity. The analgesic effect of eugenol and carvacrol is consistent with previous studies. The tendency for these chemicals to increase the avoidance of warmer temperatures suggests a possible role for TRPV3 in warmth detection, also consistent with previous studies. Additional roles of other thermosensitive TRP channels (TRPM8 TRPV1, TRPV2, TRPV4, TRPM3, TRPM8, TRPA1, TRPC5) in touch, temperature and pain are reviewed.