Transient Receptor Potential Channel Function Research Articles

Genetic and immune identification and functional analysis of TRPM8 as a potential biomarker for pancreatic adenocarcinoma proliferation.

Pancreatic adenocarcinoma (PAAD), a member of highly lethal malignant tumors, has a poor outcome and extremely poor prognosis. The transient receptor potential (TRP) superfamily, a group of nonselective cation channels, is capable of influencing cellular functions by regulating calcium homeostasis. In addition, it has been shown that TRP channels can also affect various cellular phenotypes by regulating gene transcription levels and are involved in the development of a variety of malignant tumors. In order to find new therapeutic targets and biomarkers to improve the clinical prognosis of pancreatic cancer, we performed genetic and immunological characterization of TRP channels in PAAD, as well as related functional and prognostic analyses. We investigated the expression, genetic alterations, methylation levels, and immune infiltration levels of TRP channels in PAAD, and further also analyzed the function of TRP channels in PAAD and their prognostic value for PAAD patients. Our results suggest that TRPM8 may contribute to tumor proliferation by controlling the PI3K-AKT-mTOR signaling pathway in PAAD. After careful evaluation of the accumulated data, we concluded that TRPM8 has potential as a prognostic indicator and prospective therapeutic target in PAAD.

FGF13 enhances the function of TRPV1 by stabilizing microtubules and regulates acute and chronic itch.

Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome.

Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms.

Transient receptor potential (TRP) channels are a large and diverse family of transmembrane ion channels that are widely expressed, have important physiological roles, and are associated with many human diseases. These proteins are actively pursued as promising drug targets, benefitting greatly from advances in structural and mechanistic studies of TRP channels. At the same time, the complex, polymodal activation and regulation of TRP channels have presented formidable challenges. In this short review, we summarize recent progresses toward understanding the structural basis of TRP channel function, as well as potential ligand binding sites that could be targeted for therapeutics. A particular focus is on the current understanding of the molecular mechanisms of TRP channel activation and regulation, where many fundamental questions remain unanswered. We believe that a deeper understanding of the functional mechanisms of TRP channels will be critical and likely transformative toward developing successful therapeutic strategies targeting these exciting proteins. This endeavor will require concerted efforts from computation, structural biology, medicinal chemistry, electrophysiology, pharmacology, drug safety and clinical studies.

Role of TRP Channels in Metabolism-Related Diseases.

Metabolic syndrome (MetS), with its high prevalence and significant impact on cardiovascular disease, poses a substantial threat to human health. The early identification of pathological abnormalities related to MetS and prevention of the risk of associated diseases is of paramount importance. Transient Receptor Potential (TRP) channels, a type of nonselective cation channel, are expressed in a variety of tissues and have been implicated in the onset and progression of numerous metabolism-related diseases. This study aims to review and discuss the expression and function of TRP channels in metabolism-related tissues and blood vessels, and to elucidate the interactions and mechanisms between TRP channels and metabolism-related diseases. A comprehensive literature search was conducted using keywords such as TRP channels, metabolic syndrome, pancreas, liver, oxidative stress, diabetes, hypertension, and atherosclerosis across various academic databases including PubMed, Google Scholar, Elsevier, Web of Science, and CNKI. Our review of the current research suggests that TRP channels may be involved in the development of metabolism-related diseases by regulating insulin secretion and release, lipid metabolism, vascular functional activity, oxidative stress, and inflammatory response. TRP channels, as nonselective cation channels, play pivotal roles in sensing various intra- and extracellular stimuli and regulating ion homeostasis by osmosis. They present potential new targets for the diagnosis or treatment of metabolism-related diseases.

The versatility of the putative transient receptor potential ion channels in regulating the calcium signaling in Aspergillus nidulans.

Transient receptor potential (TRP) ion channels are evolutionarily conserved integral membrane proteins with non-selective ion permeability, and they are widely distributed in mammals and single-cell yeast and serve as crucial mediators of sensory signals. However, the relevant information concerning TRP channels in Aspergillus nidulans remains inadequately understood. In this study, by gene deletion, green fluorescent protein tagging, and cytosolic Ca2+ transient monitoring techniques, the biological functions of three potential TRP channels (TrpA, TrpB, and TrpC) have been explored for which they play distinct and multiple roles in hyphal growth, conidiation, responsiveness to external stress, and regulation of intracellular Ca2+ homeostasis. The findings of this study on the functions of potential TRP channels in A. nidulans may serve as a valuable reference for understanding the roles of TRP homologs in industrial or medical strains of Aspergillus, as well as in other filamentous fungi.

Mechanosensitive channels in lung disease.

Mechanosensitive channels (MS channels) are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. In recent years, it has been found that MS channels play an important role as "sentinels" in the process of cell sensing and response to extracellular and intracellular force signals. There is growing appreciation for mechanical activation of ion channels and their subsequent initiation of downstream signaling pathways. Members of the transient receptor potential (TRP) superfamily and Piezo channels are broadly expressed in human tissues and contribute to multiple cellular functions. Both TRP and Piezo channels are thought to play key roles in physiological homeostasis and pathophysiology of disease states including in the lung. Here, we review the current state of knowledge on the expression, regulation, and function of TRP and Piezo channels in the context of the adult lung across the age spectrum, and in lung diseases such as asthma, COPD and pulmonary fibrosis where mechanical forces likely play varied roles in the structural and functional changes characteristic of these diseases. Understanding of TRP and Piezo in the lung can provide insights into new targets for treatment of pulmonary disease.

Exploring the TRP channel superfamily: research hotspots and development trends from function to disease.

Transient receptor potential (TRP) channels are a superfamily of permeable cation channels activated by various mechanisms and play a role in nearly all types of sensory signal transduction. In academia, few have comprehensively discussed the research status of TRP channels. This study aims to summarize the knowledge structure and research hotspots of TRP channels using bibliometrics. TRP channel-related publications from 2003 to 2022 were searched in the Web of Science Core Collection (WoSCC) database. VOSviewer was used for the bibliometric analysis of the literature. We included 12,242 articles from 102 countries, primarily from the United States, China, and Japan. Our research indicates that the number of publications related to TRP channels has increased annually from 2003 to 2022. The leading research institutions are KU Leuven, Harvard University, and the Chinese University of Hong Kong. The Journal of Biological Chemistry is the foremost in this field. The main research topics include the structure and function of TRP channels, their role in pathogenesis, and potential therapeutic strategies for diseases such as pain and respiratory diseases. Among these, "transient receptor potential vanilloid 1 (TRPV1)", "transient receptor potential ankyrin 1 (TRPA1)", "TRPV4", "pain", and "therapy" are emerging research hotspots. This study offers a comprehensive summary of the current research status and development trends of TRP channels and pinpoints the research hotspots in this field. It not only aids individuals interested in TRP channel-related research in quickly gauging the trends but may also guide the future research directions of researchers.

Role of TRP Channels in Liver-Related Diseases.

The liver plays a crucial role in preserving the homeostasis of an entire organism by metabolizing both endogenous and exogenous substances, a process that relies on the harmonious interactions of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (KCs), and vascular endothelial cells (ECs). The disruption of the liver's normal structure and function by diverse pathogenic factors imposes a significant healthcare burden. At present, most of the treatments for liver disease are palliative in nature, rather than curative or restorative. Transient receptor potential (TRP) channels, which are extensively expressed in the liver, play a crucial role in regulating intracellular cation concentration and serve as the origin or intermediary stage of certain signaling pathways that contribute to liver diseases. This review provides an overview of recent developments in liver disease research, as well as an examination of the expression and function of TRP channels in various liver cell types. Furthermore, we elucidate the molecular mechanism by which TRP channels mediate liver injury, liver fibrosis, and hepatocellular carcinoma (HCC). Ultimately, the present discourse delves into the current state of research and extant issues pertaining to the targeting of TRP channels in the treatment of liver diseases and other ailments. Despite the numerous obstacles encountered, TRP channels persist as an extremely important target for forthcoming clinical interventions aimed at treating liver diseases.

Targeting temperature-sensitive transient receptor potential channels in hypertension: far beyond the perception of hot and cold.

Transient receptor potential (TRP) channels are nonselective cation channels and participate in various physiological roles. Thus, changes in TRP channel function or expression have been linked to several disorders. Among the many TRP channel subtypes, the TRP ankyrin type 1 (TRPA1), TRP melastatin type 8 (TRPM8), and TRP vanilloid type 1 (TRPV1) channels are temperature-sensitive and recognized as thermo-TRPs, which are expressed in the primary afferent nerve. Thermal stimuli are converted into neuronal activity. Several studies have described the expression of TRPA1, TRPM8, and TRPV1 in the cardiovascular system, where these channels can modulate physiological and pathological conditions, including hypertension. This review provides a complete understanding of the functional role of the opposing thermo-receptors TRPA1/TRPM8/TRPV1 in hypertension and a more comprehensive appreciation of TRPA1/TRPM8/TRPV1-dependent mechanisms involved in hypertension. These channels varied activation and inactivation have revealed a signaling pathway that may lead to innovative future treatment options for hypertension and correlated vascular diseases.

6]-Gingerol Facilitates CXCL8 Secretion and ROS Production in Primary Human Neutrophils by Targeting the TRPV1 Channel.

Clarifying the function of sensory active TRP (transient receptor potential) channels in non-sensory tissue is of growing interest, especially with regard to food ingredients in nutritionally relevant concentrations. The study hypothesizes the TRPV1 agonist [6]-gingerol to facilitate cellular immune responses of primary human neutrophils, after treatment with 50nM, a concentration that can be reached in the circulation after habitual dietary intake. qRT-PCR analyses reveal a high abundancy of TRP channel RNA expression in the types of primary leukocytes investigated, namely neutrophils, monocytes, NK cells, T cells, and B cells. Incubation of neutrophils with 50nM of the known TRPV1 ligand [6]-gingerol led to increased surface expression of CD11b, CD66b, and the fMLF receptor FPR1, as shown by flow cytometry. Upon subsequent stimulation with fMLF, the neutrophils display an about 30% (p < 0.05) increase in CXCL8 secretion as well as in ROS production. Pharmacological inhibition of TRPV1 by trans-tert-butylcyclohexanol abolishes the [6]-gingerol induced effects. The TRPV1 channel is functionally expressed in human neutrophils. Activation of the channel with [6]-gingerol as a food-derived ligand in nutritionally relevant concentrations leads to an enhanced responsiveness in the cells towards activating stimuli, thereby facilitating a canonical cellular immune response in human neutrophils.

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.

Involvement of transient receptor potential channels in ocular diseases: a narrative review.

Background and ObjectiveTransient receptor potential (TRP) channels are a superfamily of functionally diverse and widely expressed cation channels which exhibit complex regulatory patterns and sensitivity to multiple environmental factors. The involvement of these ion channels is critical in various physiological functions and pathophysiological conditions. In recent decades, a growing number of studies have identified the essential role that TRP channels play in many ocular diseases. In this study, we performed a narrative review of research on the expression and function of TRP channels in various eye diseases.MethodsPubMed, Google Scholar, and Web of Science were searched for all relevant original papers and reviews published from database inception to January 31, 2022. Searches were conducted using the related keywords ‘transient receptor potential channels’, ‘TRPs’, ‘Ca2+ signaling’, ‘iron channel’, ‘TRPV4’, ‘TRPM1’, ‘retina’, ‘optic nerve’, ‘cornea’, ‘retinal ganglion cells’, ‘ON-bipolar’, ‘TRPs and retina’, ‘TRP channel and retinal ganglion cells’, ‘TRPs and cornea’, ‘diabetes’, ‘glaucoma’, ‘dry eye disease’, ‘cataract’, ‘retinopathy of prematurity’, ‘retinoblastoma’, and ‘congenital stationary night blindness’.Key Content and FindingsIn this narrative review, we summarize the history of TRP channels and introduce the TRP channel-related literature in eye disease. Next, we discuss the molecular mechanisms of TRP channels in various eye diseases and suggest future research directions.ConclusionsThe relevant studies indicate that TRP channels play vital roles in various eye diseases. However, considerable work is needed to more fully understand the functional and mechanistic aspects of how TRP channels contribute to the pathophysiology of eye disease, especially in the context of animal models and patients. Further investigations will aid in the development of future drugs targeting TRP channels for eye diseases.

The Pivotal Role of Transient Receptor Potential Channels in Oral Physiology.

Transient Receptor Potential (TRP) Channels constitute a large family of non-selective permeable ion channels involved in the perception of environmental stimuli with a central and continuously expanding role in oral tissue homeostasis. Recent studies indicate the regulatory role of TRPs in pulp physiology, oral mucosa sensation, dental pain nociception and salivary gland secretion. This review provides an update on the diverse functions of TRP channels in the physiology of the oral cavity, with emphasis on their cellular location, the underlying molecular mechanisms and clinical significance. A structured search of bibliographic databases (PubMed and MEDLINE) was performed for peer-reviewed studies on the function of TRP channels on oral cavity physiology in the last ten years. A qualitative content analysis was performed of screened papers and a critical discussion on the main findings is provided. TRPs expression has been detected in major cell types of the oral cavity, including odontoblasts, periodontal ligament, oral epithelial, salivary gland cells, and chondrocytes of temporomandibular joints, where they mediate signal perception and transduction of mechanical, thermal, and osmotic stimuli. They contribute to pulp physiology through dentin formation, mineralization, and periodontal ligament formation, along with alveolar bone remodeling in the dental pulp and periodontal ligament cells. TRPs are also involved in oral mucosa sensation, dental pain nociception, saliva secretion, swallowing reflex and temporomandibular joints' development. Various TRP channels regulate oral cavity homeostasis, playing an important role in the transduction of external stimuli to intracellular signals in a cell typespecific manner and presenting promising drug targets for the development of pharmacological strategies to manage oral diseases.

Potential of Bursera graveolens essential oil for controlling bean weevil infestations: Toxicity, repellence, and action targets

Plant essential oils are promising tools for the management of insect infestations in stored beans. However, how these biorational products exert their insecticidal actions remains unknow. Here, we evaluated the insecticidal and repellent potential of Bursera graveolens essential oil against the bean weevil species Acanthoscelides obtectus and Zabrotes subfasciatus. By using chemical and in silico analyses, we evaluated the molecular interactions of the essential oil constituents with two potential physiological targets in stored beans: acetylcholinesterase (AChE) enzymes and transient receptor potential (TRP) channels. Our results revealed limonene (44%), phellandrene (24%), cymene (13%), and menthofuran (11%) as the major constituents of the essential oil. Both bean weevil species were similarly killed by the fumigant essential oil. However, while Z. subfasciatus individuals were repelled only at high essential oil concentrations (LC95 = 156 μL/L), the essential oil LC15 (44 μL/L) was enough to repel A. obtectus individuals. Our computational predictions revealed that all essential oil constituents formed stable molecular interactions (binding affinity < −5.5 kcal/mol) with the binding sites of acetylcholinesterase and TRP channels, suggesting the involvement of these targets in the essential oil actions. Altogether, our findings show that B. graveolens essential oil may exert its insecticidal actions by disrupting the functions of AChE and TRP channels and that it may be used as an alternative tool for the control of bean weevils

Transient Receptor Potential Channels and Botulinum Neurotoxins in Chronic Pain.

Pain afflicts more than 1.5 billion people worldwide, with hundreds of millions suffering from unrelieved chronic pain. Despite widespread recognition of the importance of developing better interventions for the relief of chronic pain, little is known about the mechanisms underlying this condition. However, transient receptor potential (TRP) ion channels in nociceptors have been shown to be essential players in the generation and progression of pain and have attracted the attention of several pharmaceutical companies as therapeutic targets. Unfortunately, TRP channel inhibitors have failed in clinical trials, at least in part due to their thermoregulatory function. Botulinum neurotoxins (BoNTs) have emerged as novel and safe pain therapeutics because of their regulation of exocytosis and pro-nociceptive neurotransmitters. However, it is becoming evident that BoNTs also regulate the expression and function of TRP channels, which may explain their analgesic effects. Here, we summarize the roles of TRP channels in pain, with a particular focus on TRPV1 and TRPA1, their regulation by BoNTs, and briefly discuss the use of BoNTs for the treatment of chronic pain.

Irradiation of the Normal Murine Tongue Causes Upregulation and Activation of Transient Receptor Potential (TRP) Ion Channels.

Signal transduction at sensory neurons occurs via transmembrane flux of cations, which is largely governed by the transient receptor potential (TRP) family of ion channels. It is unknown whether TRP channel activation contributes to the pain that accompanies radiation-induced oral mucositis. This study sought to characterize changes in TRP channel expression and function that occur in the locally irradiated tissues and afferent neurons of mice. Female CD-1 mice received single high-dose (27 Gy) tongue irradiation, or sham irradiation. Animals were euthanized either before overt glossitis developed (days 1 and 5 postirradiation), when glossitis was severe (day 11), or after mice had recovered (days 21 and 45). Tongue irradiation caused upregulation of the Trpv1 gene in trigeminal ganglia (TG) neurons. Other TRP genes (Trpv2, Trpv4, Trpa1, Trpm8) and Gfrα3 (which acts upstream of several TRP channels) were also upregulated in TGs and/or tongue tissue, in response to radiation. Ex vivo calcium imaging experiments demonstrated that the proportions of TG neurons responding to histamine (an activator of TRPV1, TRPV4 and TRPA1), TNF-α (an activator of TRPV1, TRPV2 and TRPV4), and capsaicin (a TRPV1 agonist), were increased as early as one day after tongue irradiation; these changes persisted for at least 21 days. In a subsequent experiment, we found that genetic deletion of TRPV1 mitigated weight loss (a surrogate marker of pain severity) in mice with severe glossitis. The results intimate that various TRP channels, and TRPV1 in particular, should be explored as analgesic targets for patients experiencing pain after oral irradiation.

Conserved Modules Required for Drosophila TRP Function in Vivo.

Transient receptor potential (TRP) channels are broadly required in animals for sensory physiology. To provide insights into regulatory mechanisms, the structures of many TRPs have been solved. This has led to new models, some of which have been tested in vitro Here, using the classical TRP required for Drosophila visual transduction, we uncovered structural requirements for channel function in photoreceptor cells. Using a combination of molecular genetics, field recordings, protein expression analysis, and molecular modeling, we interrogated roles for the S4-S5 linker and the TRP domain, and revealed mutations in the S4-S5 linker that impair channel opening or closing. We also uncovered differential requirements for the two highly conserved motifs in the TRP domain for activation and protein stability. By performing genetic complementation, we found an intrasubunit interaction between the S4-S5 linker and the S5 segment that contributes to activation. This analysis highlights key structural requirements for TRP channel opening, closing, folding, and for intrasubunit interactions in a native context-Drosophila photoreceptor cells.SIGNIFICANCE STATEMENT The importance of TRP channels for sensory biology and human health has motivated tremendous effort in trying to understand the roles of the structural motifs essential for their activation, inactivation, and protein folding. In the current work, we have exploited the unique advantages of the Drosophila visual system to reveal mechanistic insights into TRP channel function in a native system-photoreceptor cells. Using a combination of electrophysiology (field recordings), cell biology, and molecular modeling, we have revealed roles of key motifs for activation, inactivation and protein folding of TRP in vivo.

The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis.

Brain disorders include neurodegenerative diseases (NDs) with different conditions that primarily affect the neurons and glia in the brain. However, the risk factors and pathophysiological mechanisms of NDs have not been fully elucidated. Homeostasis of intracellular Ca2+ concentration and intracellular pH (pHi) is crucial for cell function. The regulatory processes of these ionic mechanisms may be absent or excessive in pathological conditions, leading to a loss of cell death in distinct regions of ND patients. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where disrupted Ca2+ homeostasis leads to cell death. The capability of TRP channels to restore or excite the cell through Ca2+ regulation depending on the level of plasma membrane Ca2+ ATPase (PMCA) activity is discussed in detail. As PMCA simultaneously affects intracellular Ca2+ regulation as well as pHi, TRP channels and PMCA thus play vital roles in modulating ionic homeostasis in various cell types or specific regions of the brain where the TRP channels and PMCA are expressed. For this reason, the dysfunction of TRP channels and/or PMCA under pathological conditions disrupts neuronal homeostasis due to abnormal Ca2+ and pH levels in the brain, resulting in various NDs. This review addresses the function of TRP channels and PMCA in controlling intracellular Ca2+ and pH, which may provide novel targets for treating NDs.

Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal.

Free nerve endings are key structures in sensory transduction of noxious stimuli. In spite of this, little is known about their functional organization. Transient receptor potential (TRP) channels have emerged as key molecular identities in the sensory transduction of pain-producing stimuli, yet the vast majority of our knowledge about sensory TRP channel function is limited to data obtained from in vitro models which do not necessarily reflect physiological conditions. In recent years, the development of novel optical methods such as genetically encoded calcium indicators and photo-modulation of ion channel activity by pharmacological tools has provided an invaluable opportunity to directly assess nociceptive TRP channel function at the nerve terminal.

Roles of TRP Channels in Neurological Diseases.

Transient receptor potential (TRP) proteins consist of a superfamily of cation channels that have been involved in diverse physiological processes in the brain as well as in the pathogenesis of neurological disease. TRP channels are widely expressed in the brain, including neurons and glial cells, as well as in the cerebral vascular endothelium and smooth muscle. Members of this channel superfamily show a wide variety of mechanisms ranging from ligand binding to voltage, physical, and chemical stimuli, implying the promising therapeutic potential of TRP in neurological diseases. In this review, we focus on the physiological functions of TRP channels in the brain and the pathological roles in neurological disorders to explore future potential neuroprotective strategies.