Thermal Transient Receptor Potential Research Articles

Regulation of transient receptor potential channels by traditional Chinese medicines and their active ingredients.

In recent years, activation of thermal transient receptor potential (TRP) ion channels at a range of temperatures has received widespread attention as a target for traditional Chinese medicine (TCM) to regulate body temperature and relieve pain. Discovery of transient receptor potential vanilloid 1 (TRPV1) was awarded a Nobel Prize, reflecting the importance of these channels. Here, the regulatory effects of TCMs and their active ingredients on TRP ion channels are reviewed, and future directions for research on the cold, hot, warm, cool, and neutral natures of TCMs are considered. In herbs with cold, hot, warm, cool, and neutral natures, we found 29 TCMs with regulatory effects on TRP ion channels, including Cinnamomi Cortex, Capsici Fructus, Rhei Radix et Rhizoma, Macleayae cordatae Herba, Menthae Haplocalycis Herba, and Rhodiolae Crenulatae Radix et Rhizoma. Although some progress has been made in understanding the regulation of TRP ion channels by TCMs and their ingredients, the molecular mechanism by which TCMs have this effect remains to be further studied. We hope this review will provide a reference for further research on the cold, hot, warm, cool, and neutral natures of TCMs.

The effects of temperature changes on the mammalian spinal locomotor CPG network and the role of TRP channels in functional compensation

Preliminary data suggests that spinal cord neural networks that contain intact sensory pathways, which include dorsal root ganglia (DRG) and thermal transient receptor potential (TRP) channels are more resilient to gradual temperature changes than isolated preparations. Moreover, how acute temperature changes affect mammalian CPG‐driven motor activity remains uncertain. We studied how acute and gradual temperature changes impact the stability of motor networks with or without sensory pathways. More specifically, we aim to investigate: 1. the difference between how acute temperature changes versus gradual temperature changes can have an impact on the stability and robustness of motor networks; 2. how sensory inputs and TRP channels affect the adaptation of spinal central pattern generator (CPG) networks to changes in temperature. We compared changes in motor neuron bursting activity between ventral L2 and L5 roots of neonatal mouse spinal cord preparations under acute (from 20℃ directly to 29℃) and gradual (gradually from 20℃, to 23℃, to 26℃, and to 29℃) temperature change conditions. Spinal cord preparations both with and without DRGs were compared. We found that the locomotor activities were increased as temperature increase under both chronic and acute changes; however, spinal cord preparations without intact DRG showed activities with less stable phasing and more overall motor bursting variability compared to those preparations with intact DRGs (on L3, L4, and L5 spinal levels). Our results suggest that the lumbar spinal locomotor CPG network activity shows more susceptibility and less adaptation to temperature changes in the absence of sensory feedback provided by DRG sensory afferents. Further studies will be conducted in the presence of TRP channel blockers to preparations with DRGs to confirm the potential compensatory role that sensory feedback afferents convey to spinal CPG networks.

Thermo-TRPs and gut microbiota are involved in thermogenesis and energy metabolism during low temperature exposure of obese mice.

Ambient temperature and food composition can affect energy metabolism of the host. Thermal transient receptor potential ion channels (thermo-TRPs) can detect temperature signals and are involved in the regulation of thermogenesis and energy homeostasis. Further, the gut microbiota have also been implicated in thermogenesis and obesity. In the present study, we tested the hypothesis that thermo-TRPs and gut microbiota are involved in reducing diet-induced obesity (DIO) during low temperature exposure. C57BL/6J mice in obese (body mass gain >45%), lean (body mass gain <15%) and control (body mass gain <1%) groups were exposed to high (23±1°C) or low (4±1°C) ambient temperature for 28 days. Our data showed that low temperature exposure attenuated DIO, but enhanced brown adipose tissue (BAT) thermogenesis. Low temperature exposure also resulted in increased noradrenaline (NA) concentrations in the hypothalamus, decreased TRP melastatin 8 (TRPM8) expression in the small intestine, and altered composition and diversity of gut microbiota. In DIO mice, there was a decrease in overall energy intake along with a reduction in TRP ankyrin 1 (TRPA1) expression and an increase in NA concentration in the small intestine. DIO mice also showed increases in Oscillospira, [Ruminococcus], Lactococcus and Christensenella and decreases in Prevotella, Odoribacter and Lactobacillus at the genus level in fecal samples. Together, our data suggest that thermos-TRPs and gut microbiota are involved in thermogenesis and energy metabolism during low temperature exposure in DIO mice.

Moxibustion Modulates Sympathoexcitatory Cardiovascular Reflex Responses Through Paraventricular Nucleus.

Electroacupuncture (EA) point specific (ST36-37) stimulation decreases cardiovascular reflex responses through supraspinal regions such as the hypothalamic paraventricular nucleus (PVN) while mechanical stimulation of acupoints decreases pressor responses through peripheral thermal transient receptor potential vanilloid type-1 (TRPV1). Moxibustion generating heat applied at acupoint in combination with antihypertensive drugs decreases elevated blood pressure. We hypothesized that moxibustion modulates sympathoexcitatory cardiovascular responses through the hypothalamic PVN and peripheral heat sensitive TRPV1 in the absence of antihypertensive drugs. Rats were anesthetized, ventilated, and heart rate and mean blood pressure were monitored. Gastric distention induced consistent pressor reflex responses every 10-min. Thirty-minutes of bilateral moxibustion at the acupoint ST36, overlying the deep peroneal nerves, reduced the gastric distention evoked elevation in blood pressure. Blood pressure reflex responses were not reduced by both EA and moxibustion at G39. The moxibustion inhibition but not EA inhibition of the cardiovascular responses was reversed with blockade of local heat sensitive TRPV1 at ST36. Accordingly, activation of thermal TRPV1 by moxibustion at an average of 44.2°C in contrast to 40°C reduced the pressor responses. Naloxone, an opioid receptor antagonist, microinjected into PVN inhibited transiently the effect of moxibustion. Thus, activation of peripheral heat sensitive TRPV1 mediated the moxibustion-inhibition, but not EA-inhibition, of sympathoexcitatory cardiovascular reflex responses through hypothalamic PVN opioid system.

Melting Away Pain: Decay of Thermal Nociceptor Transduction during Heat-Induced Irreversible Desensitization of Ion Channels

Thermal transient receptor potential channels play a key role in thermal sensation. Although predictive models exist for temperature-dependent transduction through these channels and for the associated sensations of pain, the ability to predict irreversible desensitization has been lacking. We explored the role of irreversible ion channel desensitization in pain sensation and hypothesized that desensitization of ion channels would follow the kinetics similar to the denaturation of catalytic enzymes. We therefore proposed a three-state model to simulate the kinetic of temperature-sensitive ion channels from the closed state through opening and irreversible thermal desensitization. We tested the model against data obtained in vivo from a feline model. The theoretical model predicts all experimental data with reasonable accuracy, and represents an important step toward the ability for understanding of the molecular basis of nociceptor signaling providing the possibility to design local anesthesia regimens and to the prediction of postoperative pain.

Single-residue molecular switch for high-temperature dependence of vanilloid receptor TRPV3

Thermal transient receptor potential (TRP) channels, a group of ion channels from the transient receptor potential family, play important functions in pain and thermal sensation. These channels are directly activated by temperature and possess strong temperature dependence. Furthermore, their temperature sensitivity can be highly dynamic and use-dependent. For example, the vanilloid receptor transient receptor potential 3 (TRPV3), which has been implicated as a warmth detector, becomes responsive to warm temperatures only after intensive stimulation. Upon initial activation, the channel exhibits a high-temperature threshold in the noxious temperature range above 50 °C. This use dependence of heat sensitivity thus provides a mechanism for sensitization of thermal channels. However, how the channels acquire the use dependence remains unknown. Here, by comparative studies of chimeric channels between use-dependent and use-independent homologs, we have determined the molecular basis that underlies the use dependence of temperature sensitivity of TRPV3. Remarkably, the restoration of a single residue that is apparently missing in the use-dependent homologs could largely eliminate the use dependence of heat sensitivity of TRPV3. The location of the region suggests a mechanism of temperature-dependent gating of thermal TRP channels involving an intracellular region assembled around the TRP domain.

Modulation of Thermo-TRP Channels by Temperature in Planar Lipid Bilayers

Thermal Transient receptor potential (TRP) channels belong to the large family of TRP channels. They are an important class of receptors found widely distributed throughout the mammalian central and peripheral nervous systems. They have been shown to be directly activated by heat or cold in physiologically relevant temperature ranges, but are also activated by mechano-stimulation and various ligands. Understanding the mechanisms of temperature activation could lead to the discovery of novel compounds with differing effects on ligand activation and temperature activation for the treatment of pain and other disease states, with fewer side effects.We have employed parallel planar lipid bilayer instrumentation (Orbit, Nanion) to study different reconstituted thermo-TRP channels, particularly the purified human TRP-A1, -V1, -V3 and -M8 channels. Planar lipid bilayers can be formed by painting over Micro Electrode Cavity Array (MECA) chips, a 2 by 2 array of circular micro-cavities in a highly inert polymer. The reconstitution of the proteins is achieved by adding the purified proteins directly to the bilayers.In this study, we demonstrate the activation of the different TRP channels by cold and heat in a fully controlled environment using artificial membranes and the use of a peltier element to actively cool and heat the system to the desired temperature (±1°C). Furthermore, we compared our Q10 data from purified proteins to TRP channels expressed in HEK cells (Millipore, Chantest) using an automated patch clamp platform (Patchliner, Nanion) with temperature control.Our results support the hypothesis that temperature sensitivity is located within the channels and does not require any second messengers, including calcium or accessory proteins.

The roles of thermal transient receptor potential channels in thermotactic behavior and in thermal acclimation in the red flour beetle, Tribolium castaneum

To survive in variable or fluctuating temperature, organisms should show appropriate behavioral and physiological responses which must be mediated through properly attuned thermal sensory mechanisms. Transient receptor potential channels (TRPs) are a family of cation channels a number of which, called thermo-TRPs, are known to function as thermosensors. We investigated the potential role of thermo-TPRs that have been previously identified in the fruit fly, Drosophila melanogaster, in thermotaxis and thermal acclimation in the red flour beetle, Tribolium castaneum. Phylogenetic analysis of the trp genes showed generally one-to-one orthology between those in D. melanogaster and in T. castaneum, although there are putative gene-losses in two TRP subfamilies of D. melanogaster. With RNA interference (RNAi) of T. castaneum thermo-TRP candidates painless, pyrexia and trpA1, we measured thermal avoidance behavior. RNAi of trpA1 resulted in reduced avoidance of high temperatures, 39 and 42°C. We also measured the effects of RNAi on heat-induced knockout and death under a short exposure to high temperature (1min at 52°C) either with or without a 10-min acclimation period at 42°C. Relatively short exposure to high temperature was enough to induce high temperature thermal acclimation. RNAi of trpA1 led to faster knockout at 52°C. RNAi of painless showed lower recovery rates from heat-induced knockout after thermal acclimation, and RNAi of pyrexia showed lower long-term survivorship without thermal acclimation. Therefore, we concluded that trpA1 is important in high temperature sensing and also in enhanced tolerance to high-temperature induced knockout; painless plays a role in rapid acclimation to high temperature; and pyrexia functions in protecting beetles from acute heat stress without acclimation.

Chapter Two - Temperature Sensing by Thermal TRP Channels: Thermodynamic Basis and Molecular Insights

All organisms need to sense temperature in order to survive and adapt. But how they detect and perceive temperature remains poorly understood. Recent discoveries of thermal Transient Receptor Potential (TRP) ion channels have shed light on the problem and unravel molecular entities for temperature detection and transduction in mammals. Thermal TRP channels belong to the large family of transient receptor potential channels. They are directly activated by heat or cold in physiologically relevant temperature ranges, and the activation is exquisitely sensitive to temperature changes. Thermodynamically, this strong temperature dependence of thermal channels occurs due to large enthalpy and entropy changes associated with channel opening. Thus understanding how the channel proteins obtain their exceptionally large energetics is central toward determining functional mechanisms of thermal TRP channels. The purpose of this chapter is to provide a comprehensive review on critical issues and challenges facing the problem, with emphases on underlying biophysical and molecular mechanisms.

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

The molecular basis of the thermal sensitivity of temperature-sensitive channels appears to arise from a specific protein domain rather than integration of global thermal effects. Using systematic chimeric analysis, we show that the N-terminal region that connects ankyrin repeats to the first transmembrane segment is crucial for temperature sensing in heat-activated vanilloid receptor channels. Changing this region both transformed temperature-insensitive isoforms into temperature-sensitive channels and significantly perturbed temperature sensing in temperature-sensitive wild-type channels. Swapping other domains such as the transmembrane core, the C terminus, and the rest of the N terminus had little effect on the steepness of temperature dependence. Our results support that thermal transient receptor potential channels contain modular thermal sensors that confer the unprecedentedly strong temperature dependence to these channels.

Role of Adaptation in C. elegans thermotaxis. Focus on “Short-Term Adaptation and Temporal Processing in the Cryophilic Response of Caenorabditis elegans”

From honeybee foraging to bird migration, the orientation of animals in their environments is vital for survival and provides opportunities for studying the neural mechanisms that underlie the perception and processing of sensory information. Temperature is a ubiquitous environmental variable that