Transient Receptor Potential Family Research Articles

Widespread transcriptomic alterations of transient receptor potential channel genes in cancer.

Ion channels, in particular transient-receptor potential (TRP) channels, are essential genes that play important roles in many physiological processes. Emerging evidence has demonstrated that TRP genes are involved in a number of diseases, including various cancer types. However, we still lack knowledge about the expression alterations landscape of TRP genes across cancer types. In this review, we comprehensively reviewed and summarised the transcriptomes from more than 10000 samples in 33 cancer types. We found that TRP genes were widespreadly transcriptomic dysregulated in cancer, which was associated with clinical survival of cancer patients. Perturbations of TRP genes were associated with a number of cancer pathways across cancer types. Moreover, we reviewed the functions of TRP family gene alterations in a number of diseases reported in recent studies. Taken together, our study comprehensively reviewed TRP genes with extensive transcriptomic alterations and their functions will directly contribute to cancer therapy and precision medicine.

Primary cilia TRP channel regulates hippocampal excitability

Polycystins (PKD2, PKD2L1, and PKD2L2) are members of the transient receptor potential family, which form ciliary ion channels. Most notably, PKD2 dysregulation in the kidney nephron cilia is associated with polycystic kidney disease, but the function of PKD2L1 in neurons is undefined. In this report, we develop animal models to track the expression and subcellular localization of PKD2L1 in the brain. We discover that PKD2L1 localizes and functions as a Ca2+ channel in the primary cilia of hippocampal neurons that apically radiate from the soma. Loss of PKD2L1 expression ablates primary ciliary maturation and attenuates neuronal high-frequency excitability, which precipitates seizure susceptibility and autism spectrum disorder-like behavior in mice. The disproportionate impairment of interneuron excitability suggests that circuit disinhibition underlies the neurophenotypic features of these mice. Our results identify PKD2L1 channels as regulators of hippocampal excitability and the neuronal primary cilia as organelle mediators of brain electrical signaling.

Pruritogenic molecules in the skin of patients with dermatomyositis.

Pruritus is a common excruciating symptom in systemic autoimmune diseases such as dermatomyositis (DM) but the pathogenesis is not fully understood. We intended to investigate the targeted expression analysis of candidate molecules involved in the development of pruritus in lesional vs. non-lesional skin samples of patients affected with active DM. We looked for correlations between the investigated pruriceptive signaling molecules, disease activity, and itching sensation of DM patients. Interleukins (IL-33 and IL-6), tumor necrosis factor α (TNF-α), peroxisome proliferator-activated receptor γ (PPAR-γ), and ion channels belonging to the transient receptor potential (TRP) family were analyzed. The expression of TNF-α, PPAR-γ, IL-33, IL-6, and TRP channels in lesional DM skin was evaluated by RT-qPCR and immunohistochemistry and was compared with non-lesional DM skin samples. Pruritus, disease activity, and damage of DM were evaluated by the 5-D itch scale and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), respectively. Statistical analysis was performed with IBM SPSS 28 software. A total of 17 active DM patients participated in the study. We could show that the itching score was positively correlated with the CDASI activity score (Kendall's tau-b = 0.571; p = 0.003). TNF-α gene expression was significantly higher in lesional DM skin than in non-lesional DM skin (p = 0.009) and differed in the subgroups of patients with different itch intensities (p = 0.038). The mRNA expression of lesional IL-6 correlated positively with 5-D itch and CDASI activity score (Kendall's tau-b = 0.585; p = 0.008 and 0.45; p = 0.013, respectively). TRPV4 expressions were positively correlated with CDASI damage score (Kendall's tau-b = 0.626; p < 0.001), but the mRNA expressions of the TRP family, PPAR-γ, IL-6, and IL-33 were not different in lesional and non-lesional samples. Immunohistochemistry analysis did not find significant alterations in the expressions of TNF-α, PPAR-γ, IL-6, and IL-33 in lesional and non-lesional regions. Our results argue that cutaneous disease activity, TNF-α, and IL-6 might play a central role in DM-associated itch, while TRPV4 plays a central role in tissue regeneration.

Energetic landscape of polycystin channel gating

Members of the polycystin family (PKD2 and PKD2L1) of transient receptor potential (TRP) channels conduct Ca2+ and depolarizing monovalent cations. Variants in PKD2 cause autosomal dominant polycystic kidney disease (ADPKD) in humans, whereas loss of PKD2L1 expression causes seizure susceptibility in mice. Understanding structural and functional regulation of these channels will provide the basis for interpreting their molecular dysregulation in disease states. However, the complete structures of polycystins are unresolved, as are the conformational changes regulating their conductive states. To provide a holistic understanding of the polycystin gating cycle, we use computational prediction tools to model missing PKD2L1 structural motifs and evaluate more than 150 mutations in an unbiased mutagenic functional screen of the entire pore module. Our results provide an energetic landscape of the polycystin pore, which enumerates gating sensitive sites and interactions required for opening, inactivation, and subsequent desensitization. These findings identify the external pore helices and specific cross‐domain interactions as critical structural regulators controlling the polycystin ion channel conductive and nonconductive states.

Transient receptor potential ankyrin 1 in the knee is involved in osteoarthritis pain

Transient receptor potential families play important roles in the pathology of osteoarthritis (OA) of the knee. While transient receptor potential ankyrin 1 (TRPA1) is also an essential component of the pathogenesis of various arthritic conditions, its association with pain is controversial. Thus, we researched whether TRPA1 is involved in knee OA pain by in vivo patch–clamp recordings and evaluated the behavioral responses using CatWalk gait analysis and pressure application measurement (PAM). Injection of the Trpa1 agonist, allyl isothiocyanate (AITC), into the knee joint significantly increased spontaneous excitatory synaptic current (sEPSC) frequency in the substantia gelatinosa of rats with knee OA, while injection of the Trpa1 antagonist, HC-030031, significantly decreased the sEPSC. Meanwhile, AITC did not affect the sEPSC in sham rats. In the CatWalk and PAM behavioral tests, AITC significantly decreased pain thresholds, but no difference between HC-030031 and saline injections was observed. Our results indicate that Trpa1 mediates knee OA-induced pain. We demonstrated that Trpa1 is activated in the knee joints of rats with OA, and Trpa1 activity enhanced the pain caused by knee OA.

New Insights into the Mutual Promotion of Rosacea, Anxiety, and Depression from Neuroendocrine Immune Aspects.

Rosacea is a common chronic inflammatory skin disease with a complex etiology and undefined pathogenesis, and there is still a lack of targeted clinical treatment. Patients with rosacea are at a higher risk of anxiety and depression compared to the healthy population. Compared to skin conditions such as acne and psoriasis, rosacea has been much less studied in relation to multiple-etiology psychiatric disorders such as anxiety and depression. In contrast to the mainstream belief that the causal association between rosacea and psychiatric disorders is that rosacea increases the psychological burden of patients and thus triggers psychiatric disorders simply by altering their facial appearance, this review outlines the possible common mechanisms between rosacea and anxiety and depression disorders, starting from the pathophysiological mechanisms of transient receptor potential family cation channels, HPA axis, and Th1/Th17 cell polarization. It envisages the possibility of the neuroendocrine-immune interplay between rosacea and anxiety and depression, and new ideas on the complex causal relationship between rosacea and psychiatric disorders, offering more orientations to open up new therapeutic approaches for rosacea.

Molecular Physiology of TRPV Channels: Controversies and Future Challenges.

The ability to detect stimuli from the environment plays a pivotal role in our survival. The molecules that allow the detection of such signals include ion channels, which are proteins expressed in different cells and organs. Among these ion channels, the transient receptor potential (TRP) family responds to the presence of diverse chemicals, temperature, and osmotic changes, among others. This family of ion channels includes the TRPV or vanilloid subfamily whose members serve several physiological functions. Although these proteins have been studied intensively for the last two decades, owing to their structural and functional complexities, a number of controversies regarding their function still remain. Here, we discuss some salient features of their regulation in light of these controversies and outline some of the efforts pushing the field forward.

Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity.

Transient receptor potential (TRP) channels are involved in various physiological, pathological, and tumorigenesis-related processes. However, only a few studies have comprehensively analyzed TRP family members and their association with prognosis and tumor microenvironment (TME) in various cancers. Thus, in this study, we focused on TRP channels in pan-cancer and screened two typical TRP channels, TRPV4 and TRPC4, as examples. Based on the latest public databases, we evaluated the expression level and prognostic value of TRP family genes in pan-cancer tissues via various bioinformatic analytical methods, and investigated the relationship between the expression of TRP family genes with TME, stemness score, immune subtype, drug sensitivity, and immunotherapy outcome in pan-cancer tissues. Pan-cancer analysis revealed that the TRP family genes were differentially expressed in tumor and para-carcinoma tissues. A significant correlation existed between the expression of TRP family genes and prognosis. The expression of TRP family genes was significantly correlated with stromal, immune, RNA stemness, and DNA stemness scores in pan-cancer tissues. Our results indicated that the expression of TRP family genes correlated with the sensitivity to various drugs including PLX-4720, SB-590885, and HYPOTHEMYCIN, immunotherapy outcome, and immune-activation-related genes. Immunohistochemical analysis revealed significant differential expression of TRPV4 in bladder and para-carcinoma tissues. Our study elucidated the possible role of TRP family genes in cancer progression and provided insights for further studies on TRP family genes as potential pan-cancer targets to develop diagnostic and therapeutic strategies.

Primary cilia TRP channels regulate hippocampal excitability.

Polycystins (PKD2, PKD2L1 and PKD2L2) are members of transient receptor potential (TRP) family, which form ciliary ion channels. Most notably, PKD2 dysregulation in the kidney is associated with polycystic kidney disease but the physiological role of PKD2L1 is largely undefined. In this report, we develop animal models to track the expression and subcellular localization of these channels in the brain. We discover PKD2L1 localizes and functions as a Ca2+ channel in the primary cilia of hippocampal neurons, which apically radiate from the axon hillock. Loss of PKD2L1 expression ablates primary cilia maturation, and attenuates neuronal high frequency excitability, and precipitates seizure susceptibility and autism spectrum disorder-like behavior in mice. The disproportionate impairment of interneuron excitability suggests circuit disinhibition underlies the neurophenotypic features of these mice. Our results identify PKD2L1 channels as regulators of hippocampal excitability and the neuronal primary cilia as organelle mediators of brain electrical signaling.

Retraction Note: Transient Receptor Potential (TRP) Family of Channel Proteins

Retraction Note: Transient Receptor Potential (TRP) Family of Channel Proteins

Progress in the Structural Basis of thermoTRP Channel Polymodal Gating.

The thermosensory transient receptor potential (thermoTRP) family of ion channels is constituted by several nonselective cation channels that are activated by physical and chemical stimuli functioning as paradigmatic polymodal receptors. Gating of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity. Given that thermoTRP channels integrate diverse physical and chemical stimuli, a thorough understanding of the molecular mechanisms underlying polymodal gating has been pursued, including the interplay between stimuli and differences between family members. Despite its complexity, recent advances in cryo-electron microscopy techniques are facilitating this endeavor by providing high-resolution structures of these channels in different conformational states induced by ligand binding or temperature that, along with structure-function and molecular dynamics, are starting to shed light on the underlying allosteric gating mechanisms. Because dysfunctional thermoTRP channels play a pivotal role in human diseases such as chronic pain, unveiling the intricacies of allosteric channel gating should facilitate the development of novel drug-based resolving therapies for these disorders.

Retinal TRP channels: Cell-type-specific regulators of retinal homeostasis and multimodal integration.

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. In vertebrates, the channels are grouped into six related families: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP. As sensory transducers, TRP channels are ubiquitously expressed across the body and the CNS, mediating critical functions in mechanosensation, nociception, chemosensing, thermosensing, and phototransduction. This article surveys current knowledge about the expression and function of the TRP family in vertebrate retinas, which, while dedicated to transduction and transmission of visual information, are highly susceptible to non-visual stimuli. Every retinal cell expresses multiple TRP subunits, with recent evidence establishing their critical roles in paradigmatic aspects of vertebrate vision that include TRPM1-dependent transduction of ON bipolar signaling, TRPC6/7-mediated ganglion cell phototransduction, TRP/TRPL phototransduction in Drosophila and TRPV4-dependent osmoregulation, mechanotransduction, and regulation of inner and outer blood-retina barriers. TRP channels tune light-dependent and independent functions of retinal circuits by modulating the intracellular concentration of the 2nd messenger calcium, with emerging evidence implicating specific subunits in the pathogenesis of debilitating diseases such as glaucoma, ocular trauma, diabetic retinopathy, and ischemia. Elucidation of TRP channel involvement in retinal biology will yield rewards in terms of fundamental understanding of vertebrate vision and therapeutic targeting to treat diseases caused by channel dysfunction or over-activation.

TRPV3 and Itch: The Role of TRPV3 in Chronic Pruritus according to Clinical and Experimental Evidence

Itching is a sensory phenomenon characterized by an unpleasant sensation that makes you want to scratch the skin, and chronic itching diminishes the quality of life. In recent studies, multiple transient receptor potential (TRP) channels present in keratinocytes or nerve endings have been shown to engage in the propagation of itch signals in chronic dermatological or pruritic conditions, such as atopic dermatitis (AD) and psoriasis (PS). TRPV3, a member of the TRP family, is highly expressed in the epidermal keratinocytes. Normal TRPV3 signaling is essential for maintaining epidermal barrier homeostasis. In recent decades, many studies have suggested that TRPV3 contributes to detecting pruritus signals. Gain-of-function mutations in TRPV3 in mice and humans are characterized by severe itching, hyperkeratosis, and elevated total IgE levels. These studies suggest that TRPV3 is an important channel for skin itching. Preclinical studies have provided evidence to support the development of TRPV3 antagonists for treating inflammatory skin conditions, itchiness, and pain. This review explores the role of TRPV3 in chronic pruritus, collating clinical and experimental evidence. We also discuss underlying cellular and molecular mechanisms and explore the potential of TRPV3 antagonists as therapeutic agents.

Mining Lygus hesperus (western tarnished plant bug) transcriptomic data for transient receptor potential channels: Expression profiling and functional characterization of a Painless homolog

The transient receptor potential (TRP) family of cation channels are evolutionarily conserved proteins with critical roles in sensory physiology. Despite extensive studies in model species, knowledge of TRP channel functional diversity and physiological impact remains limited in many non-model insect species. To assess the TRP channel repertoire in a non-model agriculture pest species (Lygus hesperus), publicly available transcriptomic datasets were mined for potential homologs. Among the transcripts identified, 30 are predicted to encompass complete open reading frames that encode proteins representing each of the seven TRP channel subfamilies. Although no homologs were identified for the Pyrexia and Brivido channels, the TRP complement in L. hesperus exceeded the 13–16 channels reported in most insects. This diversity appears to be driven by a combination of alternative splicing, which impacted members of six subfamilies, and gene expansion of the TRPP subfamily. To validate the in silico data and provide more detailed analyses of L. hesperus TRP functionality, the putative Painless homolog was selected for more in depth analysis and its functional role in thermosensation examined in vitro. RT-PCR expression profiling revealed near ubiquitous expression of the Painless transcript throughout nymphal and adult development. Electrophysiological data generated using a Xenopus oocyte recombinant expression system indicated activation parameters for L. hesperus Painless homolog that are consistent with a role in noxious heat (40°–45 °C) thermosensation.

Transient Receptor Potential (TRP) Family of Channel Proteins

Transient Receptor Potential (TRP) Family of Channel Proteins

Role of TRPV1 ion channel in cervical squamous cell carcinoma genesis.

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.

Involvement of transient receptor potential in liver diseases

Transient receptor potential (TRP) family is a large superfamily of widely expressed ion channels. In recent years, several studies have been conducted on the mechanism of action of TRP. However, studies on the role of TRP in liver diseases are limited.

TRP channels: a journey towards a molecular understanding of pain.

The perception of nociceptive signals, which are translated into pain, plays a fundamental role in the survival of organisms. Because pain is linked to a negative sensation, animals learn to avoid noxious signals. These signals are detected by receptors, which include some members of the transient receptor potential (TRP) family of ion channels that act as transducers of exogenous and endogenous noxious cues. These proteins have been in the focus of the field of physiology for several years, and much knowledge of how they regulate the function of the cell types and organs where they are expressed has been acquired. The last decade has been especially exciting because the 'resolution revolution' has allowed us to learn the molecular intimacies of TRP channels using cryogenic electron microscopy. These findings, in combination with functional studies, have provided insights into the role played by these channels in the generation and maintenance of pain.

TRPs in Ovarian Serous Cystadenocarcinoma: The Expression Patterns, Prognostic Roles, and Potential Therapeutic Targets

Ovarian cancer (usually ovarian serous cystadenocarcinoma, or OV) is the fifth leading cause of cancer-related deaths in women, with more than 184,000 deaths reported worldwide annually, and is a highly malignant carcinoma. However, the mechanism of etiology remains unclear. The lack of prognostic and diagnostic biomarkers is a main limitation for clinical diagnosis and treatment. The transient receptor potential (TRP) channels play essential roles in the occurrence and development of cancers which may have the potential as a therapeutic target for OV. In our study, we used bioinformatic methods to study the potential effect and function of the TRP family in patients with OV. Differential expression analysis showed that the expression of TRPC7, TRPV4, and other TRP family members was significantly different between tumor and normal tissues. Through survival analysis, we screened out that the high expression of TRPC7, TRPV4, and TRPM (2,4,8) was negatively correlated with the prognosis of patients. In contrast, the low expression of TRPM3 was negatively associated with the prognosis. Cox regression analysis further indicated that TRPV4 was OV’s most likely therapeutic target. Finally, we conducted mRNA expression analysis, functional enrichment analysis, and immune infiltration analysis to confirm that TRPV4 was the most convincing therapeutic target of OV.

In Vitro Sensitive Skin Models: Review of the Standard Methods and Introduction to a New Disruptive Technology

The skin is a protective organ, able to decode a wide range of tactile, thermal, or noxious stimuli. Some of the sensors belonging to the transient receptor potential (TRP) family, for example, TRPV1, can elicit capsaicin-induced heat pain or histamine-induced itching sensations. The sensory nerve fibers, whose soma is located in the trigeminal or the dorsal root ganglia, are able to carry signals from the skin’s sensory receptors toward the brain via the spinal cord. In some cases, in response to environmental factors, nerve endings might be hyper activated, leading to a sensitive skin syndrome (SSS). SSS affects about 50% of the population and is correlated with small-fiber neuropathies resulting in neuropathic pain. Thus, for cosmetical and pharmaceutical industries developing SSS treatments, the selection of relevant and predictive in vitro models is essential. In this article, we reviewed the different in vitro models developed for the assessment of skin and neuron interactions. In a second part, we presented the advantages of microfluidic devices and organ-on-chip models, with a focus on the first model we developed in this context.