Showing papers on "TRPV published in 2022"
TL;DR: In this paper , a multidisciplinary approach, ranging from intracellular Ca2+ imaging to pharmacological manipulation and genetic suppression of TRPV1 expression, was adopted, to investigate the effects of photoexcitation on intracalellular Ca 2+ concentration ([Ca2+]i) in circulating ECFCs plated on rr-P3HT thin films.
14 citations
TL;DR: This work provides a classification of structurally characterized binding sites in TRPV channels and discusses the progress that has been made by structural biology combined with mutagenesis, functional recordings, and molecular dynamics simulations toward understanding of the molecular mechanisms of ligand action.
Abstract: Vanilloid-subfamily TRP channels TRPV1-6 play important roles in various physiological processes and are implicated in numerous human diseases. Advances in structural biology, particularly the “resolution revolution” in cryo-EM, have led to breakthroughs in molecular characterization of TRPV channels. Structures with continuously improving resolution uncover atomic details of TRPV channel interactions with small molecules and protein-binding partners. Here, we provide a classification of structurally characterized binding sites in TRPV channels and discuss the progress that has been made by structural biology combined with mutagenesis, functional recordings, and molecular dynamics simulations toward understanding of the molecular mechanisms of ligand action. Given the similarity in structural architecture of TRP channels, 16 unique sites identified in TRPV channels may be shared between TRP channel subfamilies, although the chemical identity of a particular ligand will likely depend on the local amino-acid composition. The characterized binding sites and molecular mechanisms of ligand action create a diversity of druggable targets to aid in the design of new molecules for tuning TRP channel function in disease conditions.
10 citations
TL;DR: Extensive genetic alterations in TRPV channel-related genes and differences in gene expression were associated with the activity of cancer marker-related pathways and were proposed novel strategies for tumor treatment.
Abstract: Background Transient Receptor Potential channels (TRPs), a class of ion channels, were first described two decades ago. Many TRP family members are major participants in nociception and integration of heat and pain signals. Recent studies have revealed that subfamilies of this channel, such as members of transient receptor potential vanilloid (TRPV) channels, play important roles in breast, ovarian, prostate, and pancreatic cancers. Methods We performed a comprehensive analysis of TRPVs in 9125 tumor samples of 33 cancer types using multi-omics data extracted from The Cancer Genome Atlas (TCGA). We identified differences in mRNA expression in a pan-cancer analysis, and the genomic characteristics of single nucleotide variations, copy number variations, methylation features, and miRNA–mRNA interactions using data from TCGA. Finally, we evaluated the sensitivity and resistance to drugs targeting TRPV channel-related genes using the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) database. Finally, we validated the drug sensitive data and the importance of TRPV6 in two cancer cell lines using q-PCR assay, CCK8 assay, EdU assay and scratch assay. Results Extensive genetic alterations in TRPV channel-related genes and differences in gene expression were associated with the activity of cancer marker-related pathways. TRPV channel-related genes can be used as prognostic biomarkers. Several potential drugs, such as lapatinib, that may target TRPV channel-related genes were identified by mining the genomics of drug sensitivity. Conclusion This study revealed the genomic changes and clinical characteristics of TRPV channel-related regulatory factors in 33 types of tumors. This analysis may help uncover the TRPV channel-related genes associated with tumorigenesis. We also proposed novel strategies for tumor treatment.
10 citations
TL;DR: These channels mediate the effects of temperature on S. salar pineal melatonin production, and their involvement in controlling the timing of daily and seasonal events in this migratory species is discussed in the context of an increasing warming of water temperatures.
Abstract: Fish are ectotherm, which rely on the external temperature to regulate their internal body temperature, although some may perform partial endothermy. Together with photoperiod, temperature oscillations, contribute to synchronizing the daily and seasonal variations of fish metabolism, physiology and behavior. Recent studies are shedding light on the mechanisms of temperature sensing and behavioral thermoregulation in fish. In particular, the role of some members of the transient receptor potential channels (TRP) is being gradually unraveled. The present study in the migratory Atlantic salmon, Salmo salar, aims at identifying the tissue distribution and abundance in mRNA corresponding to the TRP of the vanilloid subfamilies, TRPV1 and TRPV4, and at characterizing their putative role in the control of the temperature-dependent modulation of melatonin production—the time-keeping hormone—by the pineal gland. In Salmo salar, TRPV1 and TRPV4 mRNA tissue distribution appeared ubiquitous; mRNA abundance varied as a function of the month investigated. In situ hybridization and immunohistochemistry indicated specific labeling located in the photoreceptor cells of the pineal gland and the retina. Additionally, TRPV analogs modulated the production of melatonin by isolated pineal glands in culture. The TRPV1 agonist induced an inhibitory response at high concentrations, while evoking a bell-shaped response (stimulatory at low, and inhibitory at high, concentrations) when added with an antagonist. The TRPV4 agonist was stimulatory at the highest concentration used. Altogether, the present results agree with the known widespread distribution and role of TRPV1 and TRPV4 channels, and with published data on trout (Oncorhynchus mykiss), leading to suggest these channels mediate the effects of temperature on S. salar pineal melatonin production. We discuss their involvement in controlling the timing of daily and seasonal events in this migratory species, in the context of an increasing warming of water temperatures.
7 citations
TL;DR: This study may uncover TRPV channels–associated molecular mechanisms involved in the tumorigenesis and progression of ccRCC.
Abstract: Background The transient receptor potential vanilloid (TRPV) channels family, TRPV1-6, has been identified to profoundly affect a wide spectrum of pathological processes in various cancers. However, the biological function and prognostic value of TRPVs in clear cell renal cell carcinoma (ccRCC) are still largely unknown. Methods We obtained the gene expression data and clinical information of 539 ccRCC patients from The Cancer Genome Atlas (TCGA) database. A series of databases were used for data processing and visualization, including GEPIA, GeneMANIA, MethSurv, GSCA, TIMER, and starBase databases. Results The mRNA expression of TRPV2/3 was upregulated while the expression of TRPV5/6 was downregulated in ccRCC tumor tissues. TRPV family members in ccRCC were rarely mutated (nearly 7 frequencies). The ROC curve showed that TRPV2/5/6 had a high diagnostic ability in discriminating ccRCC from the control samples (AUC>0.9). Higher levels of TRPV3 expression were associated with poor prognosis of ccRCC patients, while higher expression of TRPV4 was associated with favorable prognosis. The expression of TRPV3 in normal and ccRCC tissues was validated by Immunohistochemistry, and its expression was remarkably related to high histologic grade and advanced stage. Besides, TRPV3 exhibit a reduction of DNA methylation level with tumor progression, and 12 CpGs of TRPV3 were associated with a significant prognosis. In addition, TRPV3 expression was significantly associated with the accumulation of several tumor-infiltrating immune cells, especially regulatory T cells. Furthermore, high levels of TRPV3 induced the expression of immune checkpoints such as LAG3, CTLA4, PDCD1, and TIGIT. Finally, we predicted a key SNHG3/AL513497.1-miR-10b-5p-TRPV3 axis linking to carcinogenesis and progression of ccRCC. Conclusion Our study may uncover TRPV channels–associated molecular mechanisms involved in the tumorigenesis and progression of ccRCC. TRPV family members might be diagnosed and prognostic markers and potential therapeutic targets for ccRCC patients.
7 citations
TL;DR: Capsaicin dose-dependently induced vasorelaxation of human submucosal arterioles and mouse mesenteric arterio-nervous system was investigated in this article , where the expression and function of TRPV channels in endothelial cells were examined by q-PCR, immunostaining, Ca2+ imaging and membrane potential measurements.
6 citations
TL;DR: In this article , the authors use fluorescence imaging of living worms and perform single-molecule tracking experiments to elucidate the dynamics underlying the ciliary distribution of the sensory transmembrane proteins (TPs) in the cilia of OCR-2.
Abstract: Abstract To survive, Caenorhabditis elegans depends on sensing soluble chemicals with transmembrane proteins (TPs) in the cilia of its chemosensory neurons. Cilia rely on intraflagellar transport (IFT) to facilitate the distribution of cargo, such as TPs, along the ciliary axoneme. Here, we use fluorescence imaging of living worms and perform single-molecule tracking experiments to elucidate the dynamics underlying the ciliary distribution of the sensory TP OCR-2. Quantitative analysis reveals that the ciliary distribution of OCR-2 depends on an intricate interplay between transport modes that depends on the specific location in the cilium: in dendrite and transition zone, directed transport is predominant. Along the cilium motion is mostly due to normal diffusion together with a small fraction of directed transport, while at the ciliary tip subdiffusion dominates. These insights in the role of IFT and diffusion in ciliary dynamics contribute to a deeper understanding of ciliary signal transduction and chemosensing.
6 citations
TL;DR: The results suggest LP-ICs of the bladder can perceive stretch or chemical stimuli via activation of TRPV2, TRpV4, Piezo1 and TRPA1 channels.
Abstract: The interstitial cells in bladder lamina propria (LP-ICs) are believed to be involved in sensing/afferent signaling in bladder mucosa. Transient receptor potential (TRP) cation channels act as mechano- or chemo-sensors and may underlie some of the sensing function of bladder LP-ICs. We aimed to investigate the molecular and functional expression of TRP channels implicated in bladder sensory function and Piezo1/Piezo2 channels in cultured LP-ICs of the human bladder. Bladder tissues were obtained from patients undergoing cystectomy. LP-ICs were isolated and cultured, and used for real-time reverse transcription-quantitative polymerase chain reaction, immunocytochemistry, and calcium-imaging experiments. At the mRNA level, TRPA1, TRPV2, and Piezo1 were expressed most abundantly. Immunocytochemical staining showed protein expression of TRPA1, TRPV1, TRPV2, TRPV4, TRPM8, as well as Piezo1 and Piezo2. Calcium imaging using channel agonists/antagonists provided evidence for functional expression of TRPA1, TRPV2, TRPV4, Piezo1, but not of TRPV1 or TRPM8. Activation of these channels with their agonist resulted in release of adenosine triphosphate (ATP) from LP-ICs. Inhibition of TRPV2, TRPV4 and Piezo1 blocked the stretch induced intracellular Ca2+ increase. Whereas inhibition of TRPA1 blocked H2O2 evoked response in LP-ICs. Our results suggest LP-ICs of the bladder can perceive stretch or chemical stimuli via activation of TRPV2, TRPV4, Piezo1 and TRPA1 channels. LP-ICs may work together with urothelial cells for perception and transduction of mechanical or chemical signals in human-bladder mucosa.
6 citations
TL;DR: The selected TRP proteins provide new insights in the search for targets and biomarkers needed for therapeutic strategies for PDAC treatment, suggesting that TRP channels have either tumor-suppressive or oncogenic roles.
Abstract: Pancreatic adenocarcinoma (PDAC) has low survival rates worldwide due to its tendency to be detected late and its characteristic desmoplastic reaction, which slows the use of targeted therapies. As such, the discovery of new connections between genes and the clinicopathological parameters contribute to the search for new biomarkers or targets for therapy. Transient receptor potential (TRP) channels are promising tools for cancer therapy or markers for PDAC. Therefore, in this study, we selected several genes encoding TRP proteins previously reported in cellular models, namely, Transient Receptor Potential Cation Channel Subfamily V Member 6 (TRPV6), Transient receptor potential ankyrin 1 (TRPA1), and Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), as well as the TRPM8 Channel Associated Factor 1 (TCAF1) and TRPM8 Channel Associated Factor 2 (TCAF2) proteins, as regulatory factors. We analyzed the expression levels of tumors from patients enrolled in public datasets and confirmed the results with a validation cohort of PDAC patients enrolled in the Clinical Institute Fundeni, Romania. We found significantly higher expression levels of TRPA1, TRPM8, and TCAF1/F2 in tumoral tissues compared to normal tissues, but lower expression levels of TRPV6, suggesting that TRP channels have either tumor-suppressive or oncogenic roles. The expression levels were correlated with the tumoral stages and are related to the genes involved in calcium homeostasis (Calbindin 1 or S100A4) or to proteins participating in metastasis (PTPN1). We conclude that the selected TRP proteins provide new insights in the search for targets and biomarkers needed for therapeutic strategies for PDAC treatment.
5 citations
TL;DR: In this article , the authors summarized the contribution of transient receptor potential (TRP) ion channels to the pathogenesis of asthma and proposed a novel biomarker for asthma in children, which may serve as novel therapeutic targets for this ailment.
Abstract: Transient receptor potential (TRP) ion channels play critical roles in physiological and pathological conditions. Increasing evidence has unveiled the contribution of TRP vanilloid (TRPV) family in the development of asthma. The TRPV family is a group (TRPV1-TRPV6) of polymodal channels capable of sensing thermal, acidic, mechanical stress, and osmotic stimuli. TRPVs can be activated by endogenous ligands including, arachidonic acid derivatives or endocannabinoids. While TRPV1-TRPV4 are non-selective cation channels showing a predominance for Ca2+ over Na + influx, TRPV5 and TRPV6 are only Ca2+ permeable selective channels. Asthma is a chronic inflammatory bronchopulmonary disorder involving airway hyperresponsiveness (AHR) and airway remodeling. Patients suffering from allergic asthma display an inflammatory pattern driven by cytokines produced in type-2 helper T cells (Th2) and type 2 innate lymphoid cells (ILC2s). Ion channels are essential regulators in airway smooth muscle (ASM) and immune cells physiology. In this review, we summarize the contribution of TRPV1, TRPV2, and TRPV4 to the pathogenesis of asthma. TRPV1 is associated with hypersensitivity to environmental pollutants and chronic cough, inflammation, AHR, and remodeling. TRPV2 is increased in peripheral lymphocytes of asthmatic patients. TRPV4 contributes to ASM cells proliferation, and its blockade leads to a reduced eosinophilia, neutrophilia, as well as an abolished AHR. In conclusion, TRPV2 may represent a novel biomarker for asthma in children; meanwhile, TRPV1 and TRPV4 seem to be essential contributors to the development and exacerbations of asthma. Moreover, these channels may serve as novel therapeutic targets for this ailment.
4 citations
TL;DR: Changes in the expression or activity of TRPs such as TRPCs, TRPVs, TRPMs, and TRPA channels modulate cardiac fibroblast and myofibroblasts, especially under pathological conditions.
Abstract: Cardiac fibroblasts make up a major proportion of non-excitable cells in the heart and contribute to the cardiac structural integrity and maintenance of the extracellular matrix. During myocardial injury, fibroblasts can be activated to trans-differentiate into myofibroblasts, which secrete extracellular matrix components as part of healing, but may also induce cardiac fibrosis and pathological cardiac structural and electrical remodeling. The mechanisms regulating such cellular processes still require clarification, but the identification of transient receptor potential (TRP) channels in cardiac fibroblasts could provide further insights into the fibroblast-related pathophysiology. TRP proteins belong to a diverse superfamily, with subgroups such as the canonical (TRPC), vanilloid (TRPV), melastatin (TRPM), ankyrin (TRPA), polycystin (TRPP), and mucolipin (TRPML). Several TRP proteins form non-selective channels that are permeable to cations like Na+ and Ca2+ and are activated by various chemical and physical stimuli. This review highlights the role of TRP channels in cardiac fibroblasts and the possible underlying signaling mechanisms. Changes in the expression or activity of TRPs such as TRPCs, TRPVs, TRPMs, and TRPA channels modulate cardiac fibroblasts and myofibroblasts, especially under pathological conditions. Such TRPs contribute to cardiac fibroblast proliferation and differentiation as well as to disease conditions such as cardiac fibrosis, atrial fibrillation, and fibroblast metal toxicity. Thus, TRP channels in fibroblasts represent potential drug targets in cardiac disease.
TL;DR: A significant reduction of TRPV1 expression is found in cervical squamous cell carcinoma and this expression is inversely association with the risk of cervical Squamous Cell carcinoma, indicating that TRPVs may be a potential marker of cervical cancer and a promising anti-cancer drug candidate.
Abstract: The transient receptor potential (TRP) family is a widely expressed superfamily of ion channels that regulate intracellular Ca2+ homeostasis and signal transduction. Abnormal expression of TRPV1 is closely related to malignant tumors of the female reproductive system such as breast, ovarian, cervical and endometrial cancers. In this study, we found a significant reduction of TRPV1 expression in cervical squamous cell carcinoma and this expression is inversely association with the risk of cervical squamous cell carcinoma. Furthermore, TRPV1 is involved in cell differentiation, iron death, inflammatory response, and metabolic regulation in cervical squamous cell carcinoma. Meanwhile TRPV1 is positively correlated with T cells and negatively associated with macrophages, indicating that TRPV is associated with tumor cell immunity. Therefore, TRPV1 may be a potential marker of cervical cancer and a promising anti-cancer drug candidate.
TL;DR: In this paper , it was shown that Nanchung (Nan) and Inactive (Iav) channels form complexes, which can be over-stimulated and eventually silenced by commercial insecticides, afidopyropen, pymetrozine and pyrifluquinazon.
TL;DR: This article found that Myotis ricketti bats had high levels of heat-activated transient receptor potential channels (TRPV1 and TRPV4) during torpor in winter and cold-activated TRPs (TRPM8 and TRPC5) during active states in summer.
Abstract: The ability to sense temperature changes is crucial for mammalian survival. Mammalian thermal sensing is primarily carried out by thermosensitive transient receptor potential channels (Thermo-TRPs). Some mammals hibernate to survive cold winter conditions, during which time their body temperature fluctuates dramatically. However, the underlying mechanisms by which these mammals regulate thermal responses remain unclear. Using quantitative real-time polymerase chain reaction (qRT-PCR) and the Western blotting, we found that Myotis ricketti bats had high levels of heat-activated TRPs (e.g., TRPV1 and TRPV4) during torpor in winter and cold-activated TRPs (e.g., TRPM8 and TRPC5) during active states in summer. We also found that laboratory mice had high mRNA levels of cold-activated TRPs (e.g., Trpm8 and Trpc5) under relatively hot conditions (i.e., 40 °C). These data suggest that small mammals up-regulate the expression of cold-activated TRPs even under warm or hot conditions. Binding site analysis showed that some homeobox (HOX) transcription factors (TFs) regulate the expression of hot- and cold-activated TRP genes and that some TFs of the Pit-Oct-Unc (POU) family regulate warm-sensitive and cold-activated TRP genes. The dual-luciferase reporter assay results demonstrated that TFs HOXA9, POU3F1, and POU5F1 regulate TRPC5 expression, suggesting that Thermo-TRP genes are regulated by multiple TFs of the HOX and POU families at different levels. This study provides insights into the adaptive mechanisms underlying thermal sensing used by bats to survive hibernation.
TL;DR: The authors found that Myotis ricketti bats had high levels of heat-activated transient receptor potential channels (TRPV1 and TRPV4) during torpor in winter and cold-activated TRPs (TRPM8 and TRPC5) during active states in summer.
Abstract: The ability to sense temperature changes is crucial for mammalian survival. Mammalian thermal sensing is primarily carried out by thermosensitive transient receptor potential channels (Thermo-TRPs). Some mammals hibernate to survive cold winter conditions, during which time their body temperature fluctuates dramatically. However, the underlying mechanisms by which these mammals regulate thermal responses remain unclear. Using quantitative real-time polymerase chain reaction (qRT-PCR) and the Western blotting, we found that Myotis ricketti bats had high levels of heat-activated TRPs (e.g., TRPV1 and TRPV4) during torpor in winter and cold-activated TRPs (e.g., TRPM8 and TRPC5) during active states in summer. We also found that laboratory mice had high mRNA levels of cold-activated TRPs (e.g., Trpm8 and Trpc5) under relatively hot conditions (i.e., 40 °C). These data suggest that small mammals up-regulate the expression of cold-activated TRPs even under warm or hot conditions. Binding site analysis showed that some homeobox (HOX) transcription factors (TFs) regulate the expression of hot- and cold-activated TRP genes and that some TFs of the Pit-Oct-Unc (POU) family regulate warm-sensitive and cold-activated TRP genes. The dual-luciferase reporter assay results demonstrated that TFs HOXA9, POU3F1, and POU5F1 regulate TRPC5 expression, suggesting that Thermo-TRP genes are regulated by multiple TFs of the HOX and POU families at different levels. This study provides insights into the adaptive mechanisms underlying thermal sensing used by bats to survive hibernation.感知温度变化的能力对哺乳动物的生存至关重要。哺乳动物主要是通过温度敏感型瞬时受体电位通道（Thermosensitive transient receptor potential channels, Thermo-TRPs）感应温度变化。一些哺乳类动物为了度过寒冷的冬季并存活下来会进入冬眠状态，在此期间它们的体温有剧烈波动；然而，这些哺乳动物具有哪些潜在的温度感受（thermal response）调节机制还不清楚。我们运用实时荧光聚合酶链式反应和蛋白质免疫印记等方法，发现大足鼠耳蝠（ Myotis ricketti） 在冬季蛰伏期会高表达热激活通道TRPs（例如TRPV1和TRPV4），而在夏季活跃期则高表达冷激活TRPs（例如，TRPM8和TRPC5）。我们也发现小鼠在温度相对较高的条件（40 oC）下，会高表达冷激活TRPs（例如 Trpm8 和 Trpc5 ）。这些结果提示，小型哺乳动物在温暖或较热的状况下，会上调表达冷激活TRPs。通过结合位点分析，我们发现一些同源异型盒（HOX）转录因子（Transcription factor, TF）可以调节热激活和冷激活TRPs基因的表达，而POU（Pit-Oct-Unc）家族的一些转录因子则调节温热敏感和冷激活TRPs基因的表达。双荧光素酶报告基因检测结果表明，转录因子HOXA9，POU3F1和POU5F1调节 TRPC5 的表达，可见Thermo-TRPs基因是受到HOX和POU家族中多个转录因子在不同水平上的调控。这项研究揭示蝙蝠为了在冬眠中存活下来，而采取的温度感觉适应机制。.
TL;DR: The study found that the TRPV family is an excellent prognostic stratification for ccRCC, and among them,TRPV3 is the most significant prognostic marker ofccRCC.
Abstract: ABSTRACT The transient receptor potential vanilloid (TRPV) family has been preliminarily discovered to play an important role in various cancers, including clear cell renal cell carcinoma (ccRCC), which is closely associated with immune infiltration. However, the expression and prognosis of TRPV family and tumor-infiltrating immune cells in ccRCC are obscure. This study aimed to explore the prognostic and therapeutic value of the TRPV family expression in ccRCC from the perspective of bioinformatics. We analyzed the transcriptome and clinical data of kidney renal clear cell carcinoma (KIRC) from The Cancer Genome Atlas (TCGA) database. A clustering analysis and immune infiltration analysis were conducted to investigate the influence of the TRPV family genes on ccRCC. Our study found that the TRPV family is an excellent prognostic stratification for ccRCC. Among them, TRPV3 is the most significant prognostic marker of ccRCC. In addition, we performed a drug sensitivity analysis to identify the drugs with the strongest association with TRPV3. As a result, the TRPV family, particularly TRPV3, can act as a prognostic biomarker in ccRCC to determine prognosis and levels of immune infiltration.
TL;DR: Various functions of TRPV channels, including pain sensing, temperature sensing, and metabolic control, are focused on, as well as the basal properties and pathophysiological contributions of six TRpV channels are summarized.
Abstract: Transient receptor potential vanilloid (TRPV) channels are TRP homologs and have been classified into six subfamilies. They are unique mediators of sensory signals with multiple physiological effects and are potential targets for developing new therapies targeting human diseases. TRPV channels play crucial roles in normal physiological processes, and their dysfunction has been implicated in various disease states. Several small-molecule compounds, such as TRPV1 and TRPV3 antagonists, have been developed as novel analgesic agents. A better understanding of the physiological functions of TRPV channels would lead to progress in life science. In this review, we focus on various functions of TRPV channels, including pain sensing, temperature sensing, and metabolic control, as well as summarize the basal properties and pathophysiological contributions of six TRPV channels. Moreover, we discuss the pharmacological effects of endogenous and exogenous ligands on TRPV channels and related diseases.
TL;DR: Transient receptor potential (TRP) channels are a widely expressed family of 28 evolutionarily conserved cationic ion channels that operate as primary detectors of chemical and physical stimuli and secondary effectors of metabotropic and ionotropic receptors as mentioned in this paper .
TL;DR: In this paper , the authors performed successive selection and synergism tests based on previous work and found that overexpression of the TRPV Nan gene is responsible for causing afidopyropen resistance in Bemisia tabaci.
TL;DR: In this article , the authors provided an overview on the intramolecular interactions in TRP channels and their effect on channel function, functional roles of interplays between PIP2 and other ligands and the relevance of the ligand-induced modulation of intra-drug interaction to diseases.
Abstract: The transient receptor potential (TRP) channels, classified into six (-A, -V, -P, -C, -M, -ML, -N and -Y) subfamilies, are important membrane sensors and mediators of diverse stimuli including pH, light, mechano-force, temperature, pain, taste, and smell. The mammalian TRP superfamily of 28 members share similar membrane topology with six membrane-spanning helices (S1-S6) and cytosolic N-/C-terminus. Abnormal function or expression of TRP channels is associated with cancer, skeletal dysplasia, immunodeficiency, and cardiac, renal, and neuronal diseases. The majority of TRP members share common functional regulators such as phospholipid PIP2, 2-aminoethoxydiphenyl borate (2-APB), and cannabinoid, while other ligands are more specific, such as allyl isothiocyanate (TRPA1), vanilloids (TRPV1), menthol (TRPM8), ADP-ribose (TRPM2), and ML-SA1 (TRPML1). The mechanisms underlying the gating and regulation of TRP channels remain largely unclear. Recent advances in cryogenic electron microscopy provided structural insights into 19 different TRP channels which all revealed close proximity of the C-terminus with the N-terminus and intracellular S4-S5 linker. Further studies found that some highly conserved residues in these regions of TRPV, -P, -C and -M members mediate functionally critical intramolecular interactions (i.e., within one subunit) between these regions. This review provides an overview on (1) intramolecular interactions in TRP channels and their effect on channel function; (2) functional roles of interplays between PIP2 (and other ligands) and TRP intramolecular interactions; and (3) relevance of the ligand-induced modulation of intramolecular interaction to diseases.
03 Apr 2022
TL;DR: In this paper , the authors present results from all-atom molecular dynamics simulations of ion permeation through two Ca 2+ -selective and two non-selective TRPV channels.
Abstract: The selective exchange of ions across cellular membranes is a vital biological process. Ca 2+ -mediated signalling is implicated in a broad array of physiological processes in cells, whilst elevated intracellular concentrations of Ca 2+ are cytotoxic. Due to the significance of this cation, strict Ca 2+ concentration gradients are maintained across the plasma and organelle membranes. Therefore, Ca 2+ signalling relies on permeation through selective ion channels that control the flux of Ca 2+ ions. A key family of Ca 2+ -permeable membrane channels are the polymodal signal-detecting Transient Receptor Potential (TRP) ion channels. TRP channels are activated by a wide variety of cues including temperature, small molecules, transmembrane voltage and mechanical stimuli. Whilst most members of this family permeate a broad range of cations non-selectively, TRPV5 and TRPV6 are unique due to their strong Ca 2+ -selectivity. Here, we address the question of how some members of the TRPV subfamily show a high degree of Ca 2+ -selectivity whilst others conduct a wider spectrum of cations. We present results from all-atom molecular dynamics simulations of ion permeation through two Ca 2+ -selective and two non-selective TRPV channels. Using a new method to quantify permeation co-operativity based on mutual information, we show that Ca 2+ -selective TRPV channel permeation occurs by a three binding site knock-on mechanism, whereas a two binding site knock-on mechanism is observed in non-selective TRPV channels. Each of the ion binding sites involved displayed greater affinity for Ca 2+ over Na + . As such, our results suggest that coupling to an extra binding site in the Ca 2+ -selective TRPV channels underpins their increased selectivity for Ca 2+ over Na + ions. Furthermore, analysis of all available TRPV channel structures shows that the selectivity filter entrance region is wider for the non-selective TRPV channels, slightly destabilising ion binding at this site, which is likely to underlie mechanistic decoupling.
TL;DR: The selective TRPV3 activator KS0365 triggers increases in [Ca2+ ]i with most prominent signals in the leading edge, and accelerates migration of keratinocytes, which may promote reepithelialization upon skin wounding.
Abstract: Ca2+ signalling mediated by the thermosensitive, non‐selective, Ca2+‐permeable transient receptor potential channel TRPV3 is assumed to play a critical role in regulating several aspects of skin functions, such as keratinocyte proliferation, differentiation, skin barrier formation and wound healing. Studying the function of TRPV3 in skin homeostasis, however, is still constrained by a lack of potent and selective pharmacological modulators of TRPV3.
TL;DR: In this paper , the authors present results from all-atom molecular dynamics simulations of ion permeation through two Ca2+selective and two non-selective TRPV channels.
Abstract: The selective exchange of ions across cellular membranes is a vital biological process. Ca2+-mediated signalling is implicated in a broad array of physiological processes in cells, whilst elevated intracellular concentrations of Ca2+ are cytotoxic. Due to the significance of this cation, strict Ca2+ concentration gradients are maintained across the plasma and organelle membranes. Therefore, Ca2+ signalling relies on permeation through selective ion channels that control the flux of Ca2+ ions. A key family of Ca2+-permeable membrane channels are the polymodal signal-detecting Transient Receptor Potential (TRP) ion channels. TRP channels are activated by a wide variety of cues including temperature, small molecules, transmembrane voltage and mechanical stimuli. Whilst most members of this family permeate a broad range of cations non-selectively, TRPV5 and TRPV6 are unique due to their strong Ca2+-selectivity. Here, we address the question of how some members of the TRPV subfamily show a high degree of Ca2+-selectivity whilst others conduct a wider spectrum of cations. We present results from all-atom molecular dynamics simulations of ion permeation through two Ca2+-selective and two non-selective TRPV channels. Using a new method to quantify permeation co-operativity based on mutual information, we show that Ca2+-selective TRPV channel permeation occurs by a three binding site knock-on mechanism, whereas a two binding site knock-on mechanism is observed in non-selective TRPV channels. Each of the ion binding sites involved displayed greater affinity for Ca2+ over Na+. As such, our results suggest that coupling to an extra binding site in the Ca2+-selective TRPV channels underpins their increased selectivity for Ca2+ over Na+ ions. Furthermore, analysis of all available TRPV channel structures shows that the selectivity filter entrance region is wider for the non-selective TRPV channels, slightly destabilising ion binding at this site, which is likely to underlie mechanistic decoupling.
TL;DR: In this paper , the authors reported the NMR backbone assignments of the distal TRPV4 N-terminus and noticed some discrepancies between the extent of disorder predicted solely based on protein sequence and from experimentally determined chemical shifts.
Abstract: The mammalian Transient Receptor Potential Vanilloid (TRPV) channels are a family of six tetrameric ion channels localized at the plasma membrane. The group I members of the family, TRPV1 through TRPV4, are heat-activated and exhibit remarkable polymodality. The distal N-termini of group I TRPV channels contain large intrinsically disordered regions (IDRs), ranging from ~ 75 amino acids (TRPV2) to ~ 150 amino acids (TRPV4), the vast majority of which is invisible in the structural models published so far. These IDRs provide important binding sites for cytosolic partners, and their deletion is detrimental to channel activity and regulation. Recently, we reported the NMR backbone assignments of the distal TRPV4 N-terminus and noticed some discrepancies between the extent of disorder predicted solely based on protein sequence and from experimentally determined chemical shifts. Thus, for an analysis of the extent of disorder in the distal N-termini of all group I TRPV channels, we now report the NMR assignments for the human TRPV1, TRPV2 and TRPV3 IDRs.
TL;DR: Renal TRPM2 channels have an important role in renal IR damage and deficient mice are resistant to renal IR injury, as well as being implicated in cell death caused by oxidative stress, inflammation, and apoptosis.
TL;DR: In this paper , the relationship between acupuncture and TRPV channels was discussed, and it was shown that acupuncture stimulation shows significant modulation on TRPs1 and TRPs4 at the autonomic nervous system (ANS) including central and peripheral nervous systems.
Abstract: Acupuncture is a common complementary and alternative therapy around the world, but its mechanism remains still unclear. In the past decade, some studies indicated that transient receptor potential vanilloid (TRPV) channels play a great role in the response of acupuncture stimulation. In this article, we discussed the relationship between acupuncture and TRPV channels. Different from inhibitors and agonists, the regulation of acupuncture on TRPV channels is multi-targeted and biphasic control. Acupuncture stimulation shows significant modulation on TRPV1 and TRPV4 at the autonomic nervous system (ANS) including central and peripheral nervous systems. On the contrary, the abundant expression and functional participation of TRPV1 and TRPV4 were specific to acupuncture stimulation at acupoints. The enhancement or inhibition of TRPV channels at different anatomical levels will affect the therapeutic effect of acupuncture. In conclusion, TRPV channels help to understand the principle of acupuncture stimulation, and acupuncture also provides a potential approach to TRPV-related trials.
TL;DR: In this paper , the structural dynamics rather than quiescence of transmembrane domains is necessary for capsaicin-mediated activation of transient receptor potential vanilloid 1 (TRPV1) channels.
TL;DR: The functional effects of TFNA-AM on chordotonal organs of locusts and flies are indistinguishable from those of the TRPV agonists pymetrozine, pyrifluquinazon and afidopyropen.
Abstract: BACKGROUND
The selective aphicide flonicamid is known to cause symptoms in aphids that are like those of chordotonal organ TRPV channel modulator insecticides such as pymetrozine, pyrifluquinazon and afidopyropen. Flonicamid is classified by IRAC as a chordotonal organ modulator with an undefined target site. However, while it has been shown not to act on TRPV channels, flonicamid's action on chordotonal organs has not been documented in the literature.
RESULTS
Flonicamid causes locusts to extend their hindlegs, indicating an action on the femoral chordotonal organ. In fruit flies it abolishes negative gravitaxis behavior by disrupting transduction and mechanical amplification in antennal chordotonal neurons. While flonicamid itself only weakly affects locust chordotonal organs, its major animal metabolite 4-trifluoromethylnicotinamide (TFNA-AM) potently stimulates both locust and fly chordotonal organs. Like pymetrozine, TFNA-AM rapidly increases Ca2+ in antennal chordotonal neurons in wild-type flies, but not iav1 mutants, yet the effect is non-additive with the TRPV channel agonist.
CONCLUSIONS
Flonicamid is a pro-insecticide form of TFNA-AM, a potent chordotonal organ modulator. The functional effects of TFNA-AM on chordotonal organs of locusts and flies are indistinguishable from those of the TRPV agonists pymetrozine, pyrifluquinazon and afidopyropen. Since our previous results indicate that TFNA-AM does not act directly on TRPV channels,1 we conclude that it acts upstream in a pathway that leads to TRPV channel activation. This article is protected by copyright. All rights reserved.
TL;DR: In this paper , the authors used molecular dynamics simulations to examine how one member of the TRPV family interacts with endogenous lipids and the pharmacological modulator cannabidiol (CBD).
Abstract: Transient receptor potential vanilloid (TRPV) channels play various important roles in human physiology. As membrane proteins, these channels are modulated by their endogenous lipid environment as the recent wealth of structural studies has revealed functional and structural lipid binding sites. Additionally, it has been shown that exogenous ligands can exchange with some of these lipids to alter channel gating. Here, we used molecular dynamics simulations to examine how one member of the TRPV family, TRPV2, interacts with endogenous lipids and the pharmacological modulator cannabidiol (CBD). By computationally reconstituting TRPV2 into a typical plasma membrane environment, which includes phospholipids, cholesterol, and phosphatidylinositol (PIP) in the inner leaflet, we showed that most of the interacting surface lipids are phospholipids without strong specificity for headgroup types. Intriguingly, we observed that the C‐terminal membrane proximal region of the channel binds preferentially to PIP lipids. We also modelled two structural lipids in the simulation: one in the vanilloid pocket and the other in the voltage sensor‐like domain (VSLD) pocket. The simulation shows that the VSLD lipid dampens the fluctuation of the VSLD residues, while the vanilloid lipid exhibits heterogeneity both in its binding pose and in its influence on protein dynamics. Addition of CBD to our simulation system led to an open selectivity filter and a structural rearrangement that includes a clockwise rotation of the ankyrin repeat domains, TRP helix, and VSLD. Together, these results reveal the interplay between endogenous lipids and an exogenous ligand and their effect on TRPV2 stability and channel gating.
TL;DR: In this paper , the authors discuss the structural information in the context of the function of these channels focusing on the mechanism of CaM inhibition, activation by PI(4,5)P2 and binding of pharmacological modulators.