Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing
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ABSTRACT:
SUBMITTER: Thapa D
PROVIDER: S-EPMC8592571 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The cold-induced vascular response, consisting of vasoconstriction followed by vasodilatation, is critical for protecting the cutaneous tissues against cold injury. Whilst this physiological reflex response is historic knowledge, the mechanisms involved are unclear. Here by using a murine model of local environmental cold exposure, we show that TRPA1 acts as a primary vascular cold sensor, as determined through TRPA1 pharmacological antagonism or gene deletion. The initial cold-induced vasoconstriction is mediated via TRPA1-dependent superoxide production that stimulates ?2C-adrenoceptors and Rho-kinase-mediated MLC phosphorylation, downstream of TRPA1 activation. The subsequent restorative blood flow component is also dependent on TRPA1 activation being mediated by sensory nerve-derived dilator neuropeptides CGRP and substance P, and also nNOS-derived NO. The results allow a new understanding of the importance of TRPA1 in cold exposure and provide impetus for further research into developing therapeutic agents aimed at the local protection of the skin in disease and adverse climates.
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Project description:Cold-sensitive nerve terminals (CSNTs) encode steady temperatures with regular, rhythmic temperature-dependent firing patterns that range from irregular tonic firing to regular bursting (static response). During abrupt temperature changes, CSNTs show a dynamic response, transiently increasing their firing frequency as temperature decreases and silencing when the temperature increases (dynamic response). To date, mathematical models that simulate the static response are based on two depolarizing/repolarizing pairs of membrane ionic conductance (slow and fast kinetics). However, these models fail to reproduce the dynamic response of CSNTs to rapid changes in temperature and notoriously they lack a specific cold-activated conductance such as the TRPM8 channel. We developed a model that includes TRPM8 as a temperature-dependent conductance with a calcium-dependent desensitization. We show by computer simulations that it appropriately reproduces the dynamic response of CSNTs from mouse cornea, while preserving their static response behavior. In this model, the TRPM8 conductance is essential to display a dynamic response. In agreement with experimental results, TRPM8 is also needed for the ongoing activity in the absence of stimulus (i.e. neutral skin temperature). Free parameters of the model were adjusted by an evolutionary optimization algorithm, allowing us to find different solutions. We present a family of possible parameters that reproduce the behavior of CSNTs under different temperature protocols. The detection of temperature gradients is associated to a homeostatic mechanism supported by the calcium-dependent desensitization.
| S-EPMC4591370 | biostudies-literature
Project description:It is not uncommon for patients chronically treated with opioids to exhibit opioid-induced hyperalgesia, and this has been widely reported clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small-diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in opioid-induced hyperalgesia. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels using patch clamp recording on sensory neurons and Western blot analysis on dorsal root ganglia. The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine-treated rats. Also, TRPM8 knockout mice failed to develop cold hyperalgesia after chronic administration of morphine. Our results show that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization. PERSPECTIVE:Patients receiving chronic opioid are sensitive to cold. We show in mice and rats that sustained morphine administration induces cold hyperalgesia and an upregulation of TRPM8. Knockout or selectively blocking TRPM8 reduces morphine-induced cold hyperalgesia suggesting TRPM8 is regulated by opioids.
| S-EPMC5291755 | biostudies-literature
Project description:The cold and menthol receptor, TRPM8, also designated CMR1, is a member of the transient receptor potential (TRP) family of excitatory ion channels. TRPM8 is a channel activated by cold temperatures, voltage, and menthol. In this study, we characterize the cold- and voltage-induced activation of TRPM8 channel in an attempt to identify the temperature- and voltage-dependent components involved in channel activation. Under equilibrium conditions, decreasing temperature has two effects. (i) It shifts the normalized conductance vs. voltage curves toward the left, along the voltage axis. This effect indicates that the degree of order is higher when the channel is in the open configuration. (ii) It increases the maximum channel open probability, suggesting that temperature affects both voltage-dependent and -independent pathways. In the temperature range between 18 degrees C and 25 degrees C, large changes in enthalpy (DeltaH=-112 kcal/mol) and entropy (DeltaS=-384 cal/mol K) accompany the activation process. The Q10 calculated in the same temperature range is 24. This thermodynamic analysis strongly suggests that the process of opening involves large conformational changes of the channel-forming protein. Therefore, the highly temperature-dependent transition between open and closed configurations is possible because enthalpy and entropy are both large and compensate each other. Our data also demonstrate that temperature and voltage interact allosterically to enhance channel opening.
| S-EPMC523461 | biostudies-literature
Project description:Transient receptor potential melastatin (TRPM) cation channels are polymodal sensors that are involved in a variety of physiological processes. Within the TRPM family, member 8 (TRPM8) is the primary cold and menthol sensor in humans. We determined the cryo-electron microscopy structure of the full-length TRPM8 from the collared flycatcher at an overall resolution of ~4.1 ångstroms. Our TRPM8 structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among known TRP structures, together with the carboxyl-terminal region, forms a large two-layered cytosolic ring that extensively interacts with the transmembrane channel layer. The structure suggests that the menthol-binding site is located within the voltage-sensor-like domain and thus provides a structural glimpse of the design principle of the molecular transducer for cold and menthol sensation.
| S-EPMC5810135 | biostudies-literature
Project description:Afferent nerve fibers of the somatosensory system are a molecularly diverse cell population that detects a varied range of environmental stimuli, converting these external cues ultimately into a sensory percept. Afferents mediating detection of thermal stimuli express a repertoire of temperature sensitive ion channels of the TRP family which endow these nerves with the ability to respond to the breadth of temperatures in the environment. The cold and menthol receptor TRPM8 is responsible for detection of cold and, unlike other thermosensors, detects both innocuous and noxious temperatures. How this single molecule can perform such diverse functions is currently unknown, but expression analyses in adult tissues shows that TRPM8 neurons are a molecularly diverse population and it is likely that this diversity underlies differential functionality. To determine how this phenotype is established, we examined the developmental time course of TRPM8 expression using a mouse transgenic line in which GFP expression is driven by the TRPM8 transcriptional promoter (Trpm8(GFP)). We find that Trpm8(GFP) expression begins prior to embryonic day 15.5 (E15.5) after which expression reaches levels observed in adult neurons. By E18.5, central axons of Trpm8(GFP) neurons reach the spinal cord dorsal horn, but anatomical localization and in vivo measurements of neural activity suggest that fully functional cold circuits are not established until after the first postnatal week. Additionally, Trpm8(GFP) neurons undergo a transition in neurochemical phenotype, ultimately reaching adult expression of markers such TRPV1, CGRP, peripherin, and NF200 by postnatal day 14. Thus, based on immunochemical, anatomical and functional criteria, active cold neural circuits are fully established by the second week postnatal, thereby suggesting that important extrinsic or intrinsic mechanisms are active prior to this developmental stage.
| S-EPMC2904417 | biostudies-literature
Project description:The cation channel TRPM8 plays a central role in the somatosensory system, as a key sensor of innocuously cold temperatures and cooling agents. Although increased functional expression of TRPM8 has been implicated in various forms of pathological cold hypersensitivity, little is known about the cellular and molecular mechanisms that determine TRPM8 abundance at the plasma membrane. Here we demonstrate constitutive transport of TRPM8 towards the plasma membrane in atypical, non-acidic transport vesicles that contain lysosomal-associated membrane protein 1 (LAMP1), and provide evidence that vesicle-associated membrane protein 7 (VAMP7) mediates fusion of these vesicles with the plasma membrane. In line herewith, VAMP7-deficient mice exhibit reduced functional expression of TRPM8 in sensory neurons and concomitant deficits in cold avoidance and icilin-induced cold hypersensitivity. Our results uncover a cellular pathway that controls functional plasma membrane incorporation of a temperature-sensitive TRP channel, and thus regulates thermosensitivity in vivo.
| S-EPMC4742910 | biostudies-literature
Project description:Several transient receptor potential (TRP) ion channels sense and respond to changes in ambient temperature. Chemical agonists of TRP channels, including menthol and capsaicin, also elicit sensations of temperature change. TRPM8 is a cold- and menthol-sensing ion channel that converts thermal and chemical stimuli into neuronal signals and sensations of cooling/cold. However, the expression and function of TRPM8 receptors in non-neuronal cells and tissues is a relatively unexplored area. Results presented here document the expression and function of a truncated TRPM8 variant in human bronchial epithelial cells. Expression of the TRPM8 variant was demonstrated by RT-PCR, cloning, and immunohistology. Receptor function was characterized using the prototypical TRPM8 agonist, menthol, and exposure of cells to reduced temperature (18 degrees C). The TRPM8 variant was expressed primarily within endoplasmic reticulum membranes of lung epithelial cells and its activation was attenuated by thapsigargin, the cell-permeable TRPM8 antagonist N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide, and shRNA-induced suppression of TRPM8 expression. Activation of the TRPM8 variant in lung cells was coupled with enhanced expression of the inflammatory cytokines IL-6 and IL-8. Collectively, our results suggest that this novel TRPM8 variant receptor may function as a modulator of respiratory physiology caused by cold air, and may partially explain asthmatic respiratory hypersensitivity to cold air.
| S-EPMC2551706 | biostudies-literature
Project description:Transient Receptor Potential Melastatin-8 (TRPM8) reportedly plays a fundamental role in a variety of processes including cold sensation, thermoregulation, pain transduction and tumorigenesis. However, the role of TRPM8 in inflammation under cold conditions is not well known. Since cooling allows the convergence of primary injury and injury-induced inflammation, we hypothesized that the mechanism of the protective effects of cooling might be related to TRPM8. We therefore investigated the involvement of TRPM8 activation in the regulation of inflammatory cytokines. The results showed that TRPM8 expression in the mouse hypothalamus was upregulated when the ambient temperature decreased; simultaneously, tumor necrosis factor-alpha (TNFα) was downregulated. The inhibitory effect of TRPM8 on TNFα was mediated by nuclear factor kappa B (NFκB). Specifically, cold stress stimulated the expression of TRPM8, which promoted the interaction of TRPM8 and NFκB, thereby suppressing NFκB nuclear localization. This suppression consequently led to the inhibition of TNFα gene transcription. The present data suggest a possible theoretical foundation for the anti-inflammatory role of TRPM8 activation, providing an experimental basis that could contribute to the advancement of cooling therapy for trauma patients.
| S-EPMC5362914 | biostudies-literature
Project description:BackgroundJasmonates play an important role in plant stress and defence responses and are also involved in the regulation of anthocyanin synthesis in response to sucrose availability. Here we explore the signalling interactions between sucrose and jasmonates in response to cold stress in Arabidopsis.ResultsSucrose and cold treatments increased anthocyanin content additively. Comprehensive profiling of phytohormone contents demonstrated that jasmonates, salicylic acid and abscisic acid contents increased in response to sucrose treatment in plants grown on agar, but remained considerably lower than in plants grown in compost. The gibberellin GA3 accumulated in response to sucrose treatment but only at warm temperature. The role of jasmonate signalling was explored using the jasmonate response mutants jar1-1 and coi1-16. While the jar1-1 mutant lacked jasmonate-isoleucine and jasmonate-leucine, it accumulated 12-oxo-phytodienoic acid at low temperature on agar medium. Altered patterns of abscisic acid accumulation and higher sugar contents were found in the coi1-16 mutant when grown in compost. Both mutants were able to accumulate anthocyanin and to cold acclimate, but the jar-1-1 mutant showed a larger initial drop in whole-rosette photosystem II efficiency upon transfer to low temperature.ConclusionsHormone contents are determined by interactions between temperature and sucrose supply. Some of these effects may be caused indirectly through senescence initiation in response to sucrose availability. During cold stress, the adjustments of hormone contents may compensate for impaired jasmonate signalling, enabling cold acclimation and anthocyanin accumulation in Arabidopsis jasmonate response mutants, e.g. through antagonistic interactions between gibberellin and jasmonate signalling.
| S-EPMC7178619 | biostudies-literature