Transient Receptor Potential Proteins Research Articles

Genome-wide identification, characterization, and expression analysis of the transient receptor potential gene family in mandarin fish Siniperca chuatsi

BackgroundTemperature is a crucial environmental determinant for the vitality and development of teleost fish, yet the underlying mechanisms by which they sense temperature fluctuations remain largely unexplored. Transient receptor potential (TRP) proteins, renowned for their involvement in temperature sensing, have not been characterized in teleost fish, especially regarding their temperature-sensing capabilities.ResultsIn this study, a genome-wide analysis was conducted, identifying a total of 28 TRP genes in the mandarin fish Siniperca chuatsi. These genes were categorized into the families of TRPA, TRPC, TRPP, TRPM, TRPML, and TRPV. Despite notable variations in conserved motifs across different subfamilies, TRP family members shared common structural features, including ankyrin repeats and the TRP domain. Tissue expression analysis showed that each of these TRP genes exhibited a unique expression pattern. Furthermore, examination of the tissue expression patterns of ten selected TRP genes following exposure to both high and low temperature stress indicated the expression of TRP genes were responsive to temperatures changes. Moreover, the expression profiles of TRP genes in response to mandarin fish virus infections showed significant upregulation for most genes after Siniperca chuatsi rhabdovirus, mandarin fish iridovirus and infectious spleen and kidney necrosis virus infection.ConclusionsThis study characterized the TRP family genes in mandarin fish genome-wide, and explored their expression patterns in response to temperature stress and virus infections. Our work will enhance the overall understanding of fish TRP channels and their possible functions.

TRPML1 ameliorates seizures-related neuronal injury by regulating autophagy and lysosomal biogenesis via Ca2+/TFEB signaling pathway

Alterations in autophagy have been observed in epilepsy, although their exact etiopathogenesis remains elusive. Transient Receptor Potential Mucolipin Protein 1 (TRPML1) is an ion channel protein that regulates autophagy and lysosome biogenesis. To explore the role of TRPML1 in seizures-induced neuronal injury and the potential mechanisms involved, an hyperexcitable neuronal model induced by Mg2+-free solution was used for the study. Our results revealed that TRPML1 expression was upregulated after seizures, which was accompanied by intracellular ROS accumulation, mitochondrial damage, and neuronal apoptosis. Activation of TRPML1 by ML-SA1 diminished intracellular ROS, restored mitochondrial function, and subsequently alleviated neuronal apoptosis. Conversely, inhibition of TRPML1 had the opposite effect. Further examination revealed that the accumulation of ROS and damaged mitochondria was associated with interrupted mitophagy flux and enlarged defective lysosomes, which were attenuated by TRPML1 activation. Mechanistically, TRPML1 activation allows more Ca2+ to permeate from the lysosome into the cytoplasm, resulting in the dephosphorylation of TFEB and its nuclear translocation. This process further enhances autophagy initiation and lysosomal biogenesis. Additionally, the expression of TRPML1 is positively regulated by WTAP-mediated m6A modification. Our findings highlighted crucial roles of TRPML1 and autophagy in seizures-induced neuronal injury, which provides a new target for epilepsy treatment.

The analgesic effects of Yu-Xue-Bi tablet (YXB) on mice with inflammatory pain by regulating LXA4-FPR2-TRPA1 pathway

BackgroundOxylipins including lipoxin A4 (LXA4) facilitate the resolution of inflammation and possess analgesic properties by inhibiting macrophage infiltration and transient receptor potential (TRP) protein expression. Yu-Xue-Bi Tablet (YXB) is a traditional Chinese patent medicine used to relieve inflammatory pain. Our previous research has shown that the analgesic effect of YXB is related to inhibiting peripheral inflammation and regulating macrophage infiltration, but the mechanism is not yet clear. The purpose of this study is to explore the mechanisms of YXB on mice models with Complete Freund’s Adjuvant (CFA)-induced inflammatory pain from the perspective at the resolution of inflammation.MethodsMechanical allodynia thresholds and heat hypersensitivity were measured using the Von Frey test and the hot plate test respectively. The open field test and the tail suspension test were employed to measure anxiety and depressive behaviors respectively. The expression of CD68+ and the proportion of F4/80+CD11b+ cells were measured by immunofluorescence staining and flow cytometry. The expression of transient receptor potential ankyrin 1(TRPA1) was measured by immunofluorescence staining and western blotting. Oxylipins omics analysis provided quantitative data on oxylipins in the paws, and enzyme linked immunosorbent assay (ELISA) was used to measure the levels of LXA4 there. Immunofluorescence staining was used to perform the expression of Leukotriene A4 hydroxylase (LTA4H) in the paws of mice. The impact of injecting the formyl peptide receptor 2(FPR2) antagonist WRW4 and the TRPA1 agonist AITC into the left paws was observed, focusing on the expression of mechanical allodynia thresholds, the expression of CD68+, TRPA1 in the paws, and Calcitonin gene-related peptide (CGRP) in the L5 spinal dorsal horn.ResultsYXB elevated mechanical allodynia thresholds, alleviated heat hypersensitivity and anxiety and depressive behaviors in CFA mice. It significantly reduced the number of CD68+ and proportion of F4/80+CD11b+ within the paws, thereby decreasing macrophage infiltration. Additionally, it diminished the expression of TRPA1 in the paws and TRPV1 in the DRG, leading to an inhibition of peripheral sensitization. Through quantitative analysis, it was found that YXB could modulate DHA-derived oxylipins and LXA4. ELISA results indicated that YXB elevated the levels of LXA4 and inhibited the expression of LAT4H in the paws. Furthermore, the pro-resolution and analgesic effects of YXB were hindered after administration of the FPR2 antagonist. Compared with the AITC group, YXB showed no significant improvement in anti-inflammatory and analgesic effects.ConclusionsYXB can regulate the oxylipins of paws in CFA mice to promote the resolution of inflammation. The LXA4-FPR2-TRPA1 pathway is a key mechanism for the resolution of inflammation and analgesic effects.

High humidity and NO2 co-exposure exacerbates allergic asthma by increasing oxidative stress, inflammatory and TRP protein expressions in lung tissue

Allergic asthma is a chronic inflammatory airway disease with a high mortality rate and a rapidly increasing prevalence in recent decades that is closely linked to environmental change. Previous research found that high humidity (HH) and the traffic-related air pollutant NO2 both aggregated allergic asthma. Their combined effect and mechanisms on asthma exacerbation, however, are unknown. Our study aims to toxicologically clarify the role of HH (90%) and NO2 (5 ppm) on allergic asthma. Ninety male Balb/c mice were randomly assigned to one of six groups (n = 15 in each): saline control, ovalbumin (OVA)-sensitized, OVA + HH, OVA + NO2, OVA + HH + NO2, and OVA + HH + NO2+Capsazepine (CZP). After 38 days of treatment, the airway function, pathological changes in lung tissue, blood inflammatory cells, and oxidative stress and inflammatory biomarkers were comprehensively assessed. Co-exposure to HH and NO2 exacerbated histopathological changes and airway hyperresponsiveness, increased IgE, oxidative stress markers malonaldehyde (MDA) and allergic asthma-related inflammation markers (IL-1β, TNF-α and IL-17), and upregulated the expressions of the transient receptor potential (TRP) ion channels (TRPA1, TRPV1 and TRPV4). Our findings show that co-exposure to HH and NO2 disrupted the Th1/Th2 immune balance, promoting allergic airway inflammation and asthma susceptibility, and increasing TRPV1 expression, whereas CZP reduced TRPV1 expression and alleviated allergic asthma symptoms. Thus, therapeutic treatments that target the TRPV1 ion channel have the potential to effectively manage allergic asthma.

Chief Complaint: Nasal Congestion

Nasal obstruction is the subjective perception and objective state of insufficient airflow through the nose. Nasal congestion, on the other hand, describes a state of not just inadequate airflow or obstructive phenomena but also pressure and mucus related states to the patient. Nasal receptors belonging to the transient receptor potential (TRP) protein family mediate the sense of nasal patency via the trigeminal nerve. TRPM8 responds to temperatures around 8–22 °C, and is stimulated by menthol and other cooling agents. The radiant effects of airflow create heat loss to activate these receptors and humans perceive this as nasal patency rather than the direct detection of airflow. The thermovascular state of the mucosa, in conditions such as rhinitis, influence TRPM8 activation. Nasal endoscopy can show signs of rhinitis and should be considered an essential part of the workup of nasal congestion. Efforts to relieve nasal congestion need to manage the mucosal state and surgery needs to ensures that the nasal cavity mucosa is exposed to the cooling effects of airflow rather than simply creating a passage to the nasopharynx.

Transient receptor potential (TRP) channels in Sebastes schlegelii: Genome-wide identification and ThermoTRP expression analysis under high-temperature

Transient Receptor Potential (TRP) channels, essential for sensing environmental stimuli, are widely distributed. Among them, thermosensory TRP channels play a crucial role in temperature sensing and regulation. Sebastes schlegelii, a significant aquatic economic species, exhibits sensitivity to temperature across multiple aspects. In this study, we identified 18 SsTRP proteins using whole-genome scanning. Motif analysis revealed motif 2 in all TRP proteins, with conserved motifs in subfamilies. TRP-related domains, anchored repeats, and ion-transmembrane domains were found. Chromosome analysis showed 18 TRP genes on 11 chromosomes and a scaffold. Phylogenetics classified SsTRPs into four subfamilies: TRPM, TRPA, TRPV, and TRPC. In diverse organisms, four monophyletic subfamilies were identified. Additionally, we identified key TRP genes with significantly upregulated transcription levels under short-term (30 min) and long-term (3 days) exposure at 24 °C (optimal elevated temperature) and 27 °C (critical high temperature). We propose that genes upregulated at 30 min may be involved in the primary response process of temperature sensing, while genes upregulated at 3 days may participate in the secondary response process of temperature perception. This study lays the foundation for understanding the regulatory mechanisms of TRPs responses to environmental stimuli in S. schlegelii and other fishes.

Transient receptor potential-related risk model predicts prognosis of hepatocellular carcinoma patients.

Members of the transient receptor potential (TRP) protein family shape oncogenic development, but the specific relevance of TRP-related genes in hepatocellular carcinoma (HCC) has yet to be defined. To investigate the role of TRP genes in HCC, their association with HCC development and treatment was examined. HCC patient gene expression and clinical data were downloaded from The Cancer Genome Atlas database, and univariate and least absolute shrinkage and selection operator Cox regression models were employed to explore the TRP-related risk spectrum. Based on these analyses, clinically relevant TRP family genes were selected, and the association between the key TRP canonical type 1 (TRPC1) gene and HCC patient prognosis was evaluated. In total, 28 TRP family genes were screened for clinical relevance, with multivariate analyses ultimately revealing three of these genes (TRPC1, TRP cation channel subfamily M member 2, and TRP cation channel subfamily M member 6) to be significantly associated with HCC patient prognosis (P < 0.05). These genes were utilized to establish a TRP-related risk model. Patients were separated into low- and high-risk groups based on the expression of these genes, and high-risk patients exhibited a significantly poorer prognosis (P = 0.001). Functional analyses highlighted pronounced differences in the immune status of patients in these two groups and associated enriched immune pathways. TRPC1 was identified as a candidate gene in this family worthy of further study, with HCC patients expressing higher TRPC1 levels exhibiting poorer survival outcomes. Consistently, quantitative, immunohistochemistry, and western blot analyses revealed increased TRPC1 expression in HCC. These three TRP genes help determine HCC patient prognosis, providing insight into tumor immune status and immunological composition. These findings will help design combination therapies including immunotherapeutic and anti-TRP agents.

TRP Channels in Tumoral Processes Mediated by Oxidative Stress and Inflammation.

The channels from the superfamily of transient receptor potential (TRP) activated by reactive oxygen species (ROS) can be defined as redox channels. Those with the best exposure of the cysteine residues and, hence, the most sensitive to oxidative stress are TRPC4, TRPC5, TRPV1, TRPV4, and TRPA1, while others, such as TRPC3, TRPM2, and TRPM7, are indirectly activated by ROS. Furthermore, activation by ROS has different effects on the tumorigenic process: some TRP channels may, upon activation, stimulate proliferation, apoptosis, or migration of cancer cells, while others inhibit these processes, depending on the cancer type, tumoral microenvironment, and, finally, on the methods used for evaluation. Therefore, using these polymodal proteins as therapeutic targets is still an unmet need, despite their draggability and modulation by simple and mostly unharmful compounds. This review intended to create some cellular models of the interaction between oxidative stress, TRP channels, and inflammation. Although somewhat crosstalk between the three actors was rather theoretical, we intended to gather the recently published data and proposed pathways of cancer inhibition using modulators of TRP proteins, hoping that the experimental data corroborated clinical information may finally bring the results from the bench to the bedside.

The role of endothelial TRP channels in age-related vascular cognitive impairment and dementia.

Transient receptor potential (TRP) proteins are part of a superfamily of polymodal cation channels that can be activated by mechanical, physical, and chemical stimuli. In the vascular endothelium, TRP channels regulate two fundamental parameters: the membrane potential and the intracellular Ca2+ concentration [(Ca2+)i]. TRP channels are widely expressed in the cerebrovascular endothelium, and are emerging as important mediators of several brain microvascular functions (e.g., neurovascular coupling, endothelial function, and blood-brain barrier permeability), which become impaired with aging. Aging is the most significant risk factor for vascular cognitive impairment (VCI), and the number of individuals affected by VCI is expected to exponentially increase in the coming decades. Yet, there are currently no preventative or therapeutic treatments available against the development and progression of VCI. In this review, we discuss the involvement of endothelial TRP channels in diverse physiological processes in the brain as well as in the pathogenesis of age-related VCI to explore future potential neuroprotective strategies.

Research trends in transient receptor potential vanilloid in cardiovascular disease: Bibliometric analysis and visualization.

Transient receptor potential vanilloid (TRPV) is one of the transient receptor potential protein groups; cardiovascular system disease is a crucial cause of mortality among people globally. This article is intended to accomplish a bibliometric analysis of the trends and public interest since TRPV was reported for the first time. The article summarized the Web of Science (WOS) Core Collection on the relationship between TRPV and cardiovascular system disease each year from 2000 to 2021. Data extraction and visualization were completed by R package bibliometrix. Keyword citation burst and co-citation networks were generated and produced by CiteSpace. The map evaluating the distribution of country and region was painted in GunnMap 2 (lert.co.nz). The ranking was performed using the Standard Competition Ranking method. Co-authorship and co-occurrence were analyzed with VOSviewer. After removing duplicated data, books, conference proceedings, and articles of uncertain age, 493 were included, and 17 were excluded. The pattern of publication years showed that the number of publications increased rapidly from 2008 to 2021 with no peak in the number of publications until 2021. The geographical distribution pattern revealed a considerable gap in the number of publications between the United States, China, and other countries, with East Asian institutions leading the world in this area. The pattern of co-authorship showed that 77 institutions were divided into 19 clusters, each covering one country or region.These results suggest that intercontinental cooperation among institutions should be strengthened. The core authors section displayed the change in the most published authors. Keyword analysis listed six burst keywords. Co-citation analysis of references from 2011 to 2021 showed the number and centrality of citations to leading articles. Our findings reveal trends and public interest in transient receptor potential vanilloid for cardiovascular disease. These findings suggest that the field has experienced significant growth since 2008, with the United States and China in dominant positions. Our findings also suggest that intercontinental cooperation should be strengthened, and that future research hotspots may focus on pharmacological mechanisms and in-depth exploration of drug clinical trials and new clinical disease application areas such as hypertension, diabetes, and cardiac arrhythmias, which could serve as a foundation for further research.

Deletion of classical transient receptor potential 1, 3 and 6 alters pulmonary vasoconstriction in chronic hypoxia-induced pulmonary hypertension in mice.

Chronic hypoxia-induced pulmonary hypertension (CHPH) is a severe disease that is characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling. The resulting increase in pulmonary vascular resistance (PVR) causes right ventricular hypertrophy and ultimately right heart failure. In addition, increased PVR can also be a consequence of hypoxic pulmonary vasoconstriction (HPV) under generalized hypoxia. Increased proliferation and migration of PASMCs are often associated with high intracellular Ca2+ concentration. Recent publications suggest that Ca2+-permeable nonselective classical transient receptor potential (TRPC) proteins-especially TRPC1 and 6-are crucially involved in acute and sustained hypoxic responses and the pathogenesis of CHPH. The aim of our study was to investigate whether the simultaneous deletion of TRPC proteins 1, 3 and 6 protects against CHPH-development and affects HPV in mice. We used a mouse model of chronic hypoxia as well as isolated, ventilated and perfused mouse lungs and PASMC cell cultures. Although right ventricular systolic pressure as well as echocardiographically assessed PVR and right ventricular wall thickness (RVWT) were lower in TRPC1, 3, 6-deficient mice, these changes were not related to a decreased degree of pulmonary vascular muscularization and a reduced proliferation of PASMCs. However, both acute and sustained HPV were almost absent in the TRPC1, 3, 6-deficient mice and their vasoconstrictor response upon KCl application was reduced. This was further validated by myographical experiments. Our data revealed that 1) TRPC1, 3, 6-deficient mice are partially protected against development of CHPH, 2) these changes may be caused by diminished HPV and not an altered pulmonary vascular remodeling.

Glutamatergic and GABAergic neurons in the preoptic area of the hypothalamus play key roles in menopausal hot flashes.

During menopause, when estrogen levels are low, abnormalities in the hypothalamic preoptic area (POA) of the thermoregulatory center can cause hot flashes. However, the involved neural population has not been identified. Proteomics showed that under low estrogen, differentially expressed proteins in the hypothalamus were associated with glutamatergic and GABAergic synapses. RNAscope, Western blotting and qRT-PCR indicated that the number of glutamatergic neurons in the POA was decreased, while the number of GABAergic neurons was increased. Chemogenetics showed that the rat body temperature decreased slowly after glutamatergic neurons were activated and increased quickly after glutamatergic neurons were inhibited, while it increased quickly after GABAergic neurons were activated and decreased slowly after GABAergic neurons were inhibited. RNAscope, immunofluorescence, Western blotting and qRT-PCR further showed that glutamate decarboxylase (GAD) 1 expression in the POA was increased, while GAD2 expression in the POA was decreased; that thermosensitive transient receptor potential protein (ThermoTRP) M (TRPM) 2 expression in glutamatergic neurons was decreased, while TRPM8 expression in GABAergic neurons was increased; and that estrogen receptor (ER) α and β expression in the POA was decreased, and ERα and ERβ expressed in both glutamatergic and GABAergic neurons. Estrogen therapy corrected these abnormalities. In addition, CUT&Tag and Western blot after injection of agonists and inhibitors of ERs showed that ERα and ERβ were both transcription factors in glutamatergic and GABAergic synapses. Mechanistically, during menopause, estrogen may regulate the transcription and expression of GADs and ThermoTRPs through ERs, impacting the number and function of glutamatergic and GABAergic neurons, resulting in unbalanced heat dissipation and production in the POA and ultimately triggering hot flashes.

Emerging role of transient receptor potential (TRP) ion channels in cardiac fibroblast pathophysiology.

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.

Function and therapeutic potential of transient receptor potential ankyrin 1 in fibrosis.

The transient receptor potential (TRP) protein superfamily is a special group of cation channels expressed in different cell types and signaling pathways. In this review, we focus on TRPA1 (transient receptor potential ankyrin 1), an ion channel in this family that exists in the cell membrane and shows a different function from other TRP channels. TRPA1 usually has a special activation effect that can induce cation ions, especially calcium ions, to flow into activated cells. In this paper, we review the role of TRPA1 in fibroblasts. To clarify the relationship between fibroblasts and TRPA1, we have also paid special attention to the interactions between TRPA1 and inflammatory factors leading to fibroblast activation. TRPA1 has different functions in the fibrosis process in different organs, and there have also been interesting discussions of the mechanism of TRPA1 in fibroblasts. Therefore, this review aims to describe the function of TRP channels in controlling fibrosis through fibroblasts in different organ inflammatory and immune-mediated diseases. We attempt to prove that TRPA1 is a target for fibrosis. In fact, some clinical trials have already proven that TRPA1 is a potential adjuvant therapy for treating fibrosis.

The Association between TRP Channels Expression and Clinicopathological Characteristics of Patients with Pancreatic Adenocarcinoma.

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.

Protective Mechanism of Electroacupuncture on Peripheral Neurotoxicity Induced by Oxaliplatin in Rats.

To study the effect of electroacupuncture (EA) on oxaliplatin-induced peripheral neuropathy (OIPN) in rats. Male Sprague-Dawley rats were equally divided into 3 groups using a random number table: the control group, the OIPN group, and the EA (OIPN + EA) group, with 10 rats in each. The time courses of mechanical, cold sensitivity, and microcirculation blood flow intensity were determined. The morphology of the dorsal root ganglion (DRG) was observed by electron microscopic examination. The protein levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the transient receptor potential (TRP) protein family in DRGs were assayed by Western blot. EA treatment significantly reduced mechanical allodynia and cold allodynia in OIPN rats (P<0.01). Notably, oxaliplatin treatment resulted in impaired microcirculatory blood flow and pathomorphological defects in DRGs (P<0.01). EA treatment increased the microcirculation blood flow and attenuated the pathological changes induced by oxaliplatin (P<0.01). In addition, the expression levels of Nrf2 and HO-1 were down-regulated, and the TRP protein family was over-expressed in the DRGs of OIPN rats (P<0.01). EA increased the expression levels of Nrf2 and HO-1 and decreased the level of TRP protein family in DRG (P<0.05 or P<0.01). EA may be a potential alternative therapy for OIPN, and its mechanism may be mainly mediated by restoring the Nrf2/HO-1 signaling pathway.

Antirheumatoid Arthritic Effects of Sabia parviflora Wall. Leaf Extracts via the NF-κB Pathway and Transient Receptor Potential Protein Family.

As an important traditional medicine of Buyi and Miao ethnic groups in Guizhou, Sabia parviflora Wall. provides antiviral properties against hepatitis, eliminates wind and dampness, and exhibits anti-inflammatory and pain relief properties. It has also been shown to treat rheumatoid arthritis (RA) and other diseases. However, the pharmacodynamic mechanism of S. parviflora Wall. for RA has not been reported. In this study, we identified the effective compounds of S. parviflora Wall. leaves against RA and discussed the mechanism against complete Freund’s adjuvant-induced arthritis (AIA) based on inflammatory proteins and transient receptor potential (TRP) proteins. S. parviflora Wall. leaf extracts (0.64 g/kg, 0.32 g/kg, and 0.16 g/kg, once daily) were given orally for 21 days. On the 15th day of complete Freund’s adjuvant-induced RA, the effects of this medicine on RA rats were investigated. S. parviflora Wall. extracts increased body weight, decreased foot swelling, and reduced thymus and spleen indices in model rats. Most of pannus in the synovial tissue of RA rats disappeared upon treatment, and the local inflammatory cells were greatly reduced when given the fraction of n-butanol (0.64 g/kg/d, 0.32 g/kg/d, and 0.16 g/kg/d) of 70% alcohol-soluble fraction of S. parviflora Wall. leaves. In addition, the release of inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-15 (IL-15), and vascular endothelial growth factor (VEGF) in the RA rat serum was inhibited. The active compounds inhibited the expression of TNF-α, IL-1β, IL-6, IL-10, IL-15 and nuclear factor kappa-Bp65 (NF-κBp65) inflammatory protein and TRP protein transient receptor potential melastatin-5 (TRPM-5) and transient receptor potential channel-6 (TRPC-6), to reduce the expression of VEGF in synovial tissue of RA rats and relieve redness and edema. High-performance liquid chromatography identified six flavonoids and three triterpenoid saponins as active compounds. These findings suggest S. parviflora Wall. leaves may play a role in RA treatment by inhibiting the release of inflammatory factors as well as participating in the inflammatory protein expression in the NF-κB pathway and TRP protein family.

Sequence and structural conservation reveal fingerprint residues in TRP channels.

Transient receptor potential (TRP) proteins are a large family of cation-selective channels, surpassed in variety only by voltage-gated potassium channels. Detailed molecular mechanisms governing how membrane voltage, ligand binding, or temperature can induce conformational changes promoting the open state in TRP channels are still a matter of debate. Aiming to unveil distinctive structural features common to the transmembrane domains within the TRP family, we performed phylogenetic reconstruction, sequence statistics, and structural analysis over a large set of TRP channel genes. Here, we report an exceptionally conserved set of residues. This fingerprint is composed of twelve residues localized at equivalent three-dimensional positions in TRP channels from the different subtypes. Moreover, these amino acids are arranged in three groups, connected by a set of aromatics located at the core of the transmembrane structure. We hypothesize that differences in the connectivity between these different groups of residues harbor the apparent differences in coupling strategies used by TRP subgroups.

Polycystin-2 (TRPP2): Ion channel properties and regulation.

Polycystin-2 (TRPP2, PKD2, PC2) is the product of the PKD2 gene, whose mutations cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). PC2 belongs to the superfamily of TRP (Transient Receptor Potential) proteins that generally function as Ca2+-permeable nonselective cation channels implicated in Ca2+ signaling. PC2 localizes to various cell domains with distinct functions that likely depend on interactions with specific channel partners. Functions include receptor-operated, nonselective cation channel activity in the plasma membrane, intracellular Ca2+ release channel activity in the endoplasmic reticulum (ER), and mechanosensitive channel activity in the primary cilium of renal epithelial cells. Here we summarize our current understanding of the properties of PC2 and how other transmembrane and cytosolic proteins modulate this activity, providing functional diversity and selective regulatory mechanisms to its role in the control of cellular Ca2+ homeostasis.

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies.

Transient receptor potential (TRP) proteins are a large group of ion channels that control many physiological functions in our body. These channels are considered potential therapeutic drug targets for various diseases such as neurological disorders, cancers, cardiovascular disease, and many more. The Nobel Prize in Physiology/Medicine in the year 2021 was awarded to two scientists for the discovery of TRP and PIEZO ion channels. Improving our knowledge of technologies for their study is essential. In the present study, we reviewed the role of TRP channel types in the control of normal physiological functions as well as disease conditions. Also, we discussed the current and novel technologies that can be used to study these channels successfully. As such, Flux assays for detecting ionic flux through ion channels are among the core and widely used tools for screening drug compounds. Technologies based on these assays are available in fully automated high throughput set-ups and help detect changes in radiolabeled or non-radiolabeled ionic flux. Aurora’s Ion Channel Reader (ICR), which works based on label-free technology of flux assay, offers sensitive, accurate, and reproducible measurements to perform drug ranking matching with patch-clamp (gold standard) data. The non-radiolabeled trace-based flux assay coupled with the ICR detects changes in various ion types, including potassium, calcium, sodium, and chloride channels, by using appropriate tracer ions. This technology is now considered one of the very successful approaches for analyzing ion channel activity in modern drug discovery. It could be a successful approach for studying various ion channels and transporters, including the different members of the TRP family of ion channels.