Regulation Of Transient Receptor Potential Channels Research Articles

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.

Phosphoinositide Regulation of TRP Channels: A Functional Overview in the Structural Era.

Transient receptor potential (TRP) ion channels have diverse activation mechanisms including physical stimuli, such as high or low temperatures, and a variety of intracellular signaling molecules. Regulation by phosphoinositides and their derivatives is their only known common regulatory feature. For most TRP channels, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] serves as a cofactor required for activity. Such dependence on PI(4,5)P2 has been demonstrated for members of the TRPM subfamily and for the epithelial TRPV5 and TRPV6 channels. Intracellular TRPML channels show specific activation by PI(3,5)P2. Structural studies uncovered the PI(4,5)P2 and PI(3,5)P2 binding sites for these channels and shed light on the mechanism of channel opening. PI(4,5)P2 regulation of TRPV1-4 as well as some TRPC channels is more complex, involving both positive and negative effects. This review discusses the functional roles of phosphoinositides in TRP channel regulation and molecular insights gained from recent cryo-electron microscopy structures.

Impact of lipid rafts on transient receptor potential channel activities.

Members of the transient receptor potential (TRP) superfamily are cation channels that are expressed in nearly every mammalian cell type and respond as cellular sensors to various environmental stimuli. Light, pressure, osmolarity, temperature, and other stimuli can induce TRP calcium conductivity and correspondingly trigger many signaling processes in cells. Disruption of TRP channel activity, as a rule, harms cellular function. Despite numerous studies, the mechanisms of TRP channel regulation are not yet sufficiently clear, in part, because TRP channels are regulated by a broad set of ligands having diverse physical and chemical features. It is now known that some TRP members are located in membrane microdomains termed lipid rafts. Moreover, interaction between specific raft-associated lipids with channels may be a key regulation mechanism. This review examines recent findings related to the roles of lipid rafts in regulation of TRP channel activity. The mechanistic events of channel interactions with the main lipid raft constituent, cholesterol, are being clarified. Better understanding of mechanisms behind such interactions would help establish the key elements of TRP channel regulation and hence allow control of cellular responses to environmental stimuli.

Selenium and Neurological Diseases: Focus on Peripheral Pain and TRP Channels.

Pain is a complex physiological process that includes many components. Growing evidence supports the idea that oxidative stress and Ca2+ signaling pathways participate in pain detection by neurons. The main source of endogenous reactive oxygen species (ROS) is mitochondrial dysfunction induced by membrane depolarization, which is in turn caused by Ca2+ influx into the cytosol of neurons. ROS are controlled by antioxidants, including selenium. Selenium plays an important role in the nervous system, including the brain, where it acts as a cofactor for glutathione peroxidase and is incorporated into selenoproteins involved in antioxidant defenses. It has neuroprotective effects through modulation of excessive ROS production, inflammation, and Ca2+ overload in several diseases, including inflammatory pain, hypersensitivity, allodynia, diabetic neuropathic pain, and nociceptive pain. Ca2+ entry across membranes is mediated by different channels, including transient receptor potential (TRP) channels, some of which (e.g., TRPA1, TRPM2, TRPV1, and TRPV4) can be activated by oxidative stress and have a role in the induction of peripheral pain. The results of recent studies indicate the modulator roles of selenium in peripheral pain through inhibition of TRP channels in the dorsal root ganglia of experimental animals. This review summarizes the protective role of selenium in TRP channel regulation, Ca2+ signaling, apoptosis, and mitochondrial oxidative stress in peripheral pain induction.

Dysfunction of transient receptor potential ion channels as an important pathophysiological mechanism in asthma

Asthma is a chronic heterogeneous disease characterized by chronic inflammation and bronchial hyperreactivity. Neurogenic inflammation is one of the important causes of hyperreactivity. Dysfunction of transient receptor potential (TRP) ion channels underlies the development of neurogenic inflammation, bronchial hyperreactivity and respiratory symptoms of asthma such as bronchospasm and cough. TRP channels are expressed in the respiratory tract. Their activation is mediated by endogenous and exogenous factors involved in the pathogenesis of asthma. The study of functioning and regulation of TRP channels is relevant, as they could be important therapeutic targets for asthma. The aim of the review is to summarize modern ideas about the mechanisms of functioning and regulation of members of the TRP channel superfamily, the role of which in lung pathology and physiology are the best studied.

Structural and Evolutionary Insights Point to Allosteric Regulation of TRP Ion Channels.

The familiar pungent taste of spicy food, the refreshing taste of mint, and many other physiological phenomena are mediated by transient receptor potential (TRP) ion channels. TRP channels are a superfamily of ion channels that are sensitive to diverse chemical and physical stimuli and play diverse roles in biology. In addition to chemical regulation, some family members also sense common physical stimuli, such as temperature or pressure. Since their discovery and cloning in the 1990s and 2000s, understanding the molecular mechanisms governing TRP channel function and polymodal regulation has been a consistent but challenging goal. Until recently, a general lack of high-resolution TRP channel structures had significantly limited a molecular understanding of their function. In the past few years, a flood of TRP channel structures have been released, made possible primarily by advances in cryo-electron microscopy (cryo-EM). The boon of many structures has unleashed unparalleled insight into TRP channel architecture. Substantive comparative studies between TRP structures provide snapshots of distinct states such as ligand-free, stabilized by chemical agonists, or antagonists, partially illuminating how a given channel opens and closes. However, the now ∼75 TRP channel structures have ushered in surprising outcomes, including a lack of an apparent general mechanism underlying channel opening and closing among family members. Similarly, the structures reveal a surprising diversity in which chemical ligands bind TRP channels. Several TRP channels are activated by temperature changes in addition to ligand binding. Unraveling mechanisms of thermosensation has proven an elusive challenge to the field. Although some studies point to thermosensitive domains in the transmembrane region of the channels, results have sometimes been contradictory and difficult to interpret; in some cases, a domain that proves essential for thermal sensitivity in one context can be entirely removed from the channel without affecting thermosensation in another context. These results are not amenable to simple interpretations and point to allosteric networks of regulation within the channel structure. TRP channels have evolved to be fine-tuned for the needs of a species in its environmental niche, a fact that has been both a benefit and burden in unlocking their molecular features. Functional evolutionary divergence has presented challenges for studying TRP channels, as orthologs from different species can give conflicting experimental results. However, this diversity can also be examined comparatively to decipher the basis for functional differences. As with structural biology, untangling the similarities and differences resulting from evolutionary pressure between species has been a rich source of data guiding the field. This Account will contextualize the existing biochemical and functional data with an eye to evolutionary data and couple these insights with emerging structural biology to better understand the molecular mechanisms behind chemical and physical regulation of TRP channels.

Potential therapeutic value of transient receptor potential channels in male urogenital system.

Transient receptor potential (TRP) channels comprise a family of cation channels implicated in a variety of cellular processes including light, mechanical or chemical stimuli, temperature, pH, or osmolarity. TRP channel proteins are a diverse family of proteins that are expressed in many tissues. We debated our recent knowledge about the expression, function, and regulation of TRP channels in the different parts of the male urogenital system in health and disease. Emerging evidence suggests that dysfunction ofTRP channels significantly contributes to the pathophysiology of urogenital diseases. So far, there are many efforts underway to determine if these channels can be used as drug targets to reverse declines in male urogenital function. Furthermore, developing safe and efficacious TRP channel modulators is warranted for male urogenital disorders in a clinical setting.

Pathophysiology of cation channels in pain: Focus on TRP Channels

In neurons such as dorsal root ganglion (DRG) and trigeminal ganglia, calcium (Ca2+) and sodium ion concentrations are higher in in outside than in cytosol, although potassium ion concentration was higher in inside of the neurons than outside of the neurons. Within the ions, it has been suggested that a dysregulation of Ca2+ homeostasis acts a key role in the pathogenesis of oxidative stress associated nerve damage. Ca2+ is a main intracellular messenger involved in several physiological functions of neurons such survival, death, synaptic plasticity and neurotransmitter release. It has specific role in induction of peripheral pain. Ca2+ passes cell membrane via different channels such as chemical and voltage gated channels. Apart from the well-known cation channels, there is recently discovered channels namely transient receptor potential (TRP) family. The TRP superfamily is containing 6 subfamilies with 28 members in mammalian. Activation and inhibition mechanisms of the TRP channels are very different from the voltage gated calcium channels. Some TRP channels such as TRP melastatin 2 (TRPM2), melastatin 7 (TRPM7) and TRP ankyrin 1 (TRPA1) are activated by oxidative stress. Expression levels of TRPA1, TRPM2 and TRPM7 are high in DRG, phagocytic cells and hippocampus, respectively. Therefore, TRPM2 is important channels in physiological activity of phagocytic cells such as neutrophil and monocytes (Heiner et al. 2006). TRPM7 and TRPA1 have main roles in cerebral ischemia and peripheral pain molecular pathways, respectively (Carrasco et al. 2018; Sun, 2017). Till today specific antagonists of most TRP channels have not been discovered yet and they have potential targets for discovering drugs in neuroscience. In pain etiology, Ca2+ is important and it has been demonstrated in some studies that the administration of an antagonist to Ca2+ channels induces a reduction in chemotherapeutic  agents-induced neuropathic pain.  In the presentation, I discussed novel results of Ca2+ on the peripheral pain by the regulation of TRP channels.  I concluded that the results of recent studies suggest that increased cytosolic Ca2+ has through inhibition of TRP channels main role in etiology of peripheral pain. It seems to that the TRP channels are potential target for treatment of peripheral pain. 

Involvement of Thermo TRP channels on chemothrepeutic agents-induced peripheral pain

Accumulating evidences have indicated that disturbances in intracellular free calcium ([Ca2+]i) concentration play an important role in the pathophysiology of peripheral pain. Ca2+ passes cell membrane via different channels such as chemical and voltage gated channels. Apart from the well-known cation channels, there is recently discovered channels namely transient receptor potential (TRP) family. At least, 11 TRP channels in mammalian cells have been identified as thermosensitive TRP (thermo-TRP) channels (Uchida et al. 2017). Two TRP channels (TRPV1 and TRPV2) are activated by high temperatures. Five TRP channels (TRPV1-4 and TRPM2) are activated by different heat temperatures, although two of TRP channels (TRPA1 and TRPM8) are activated by cold and cool temperatures, respectively (Nazıroğlu and Braidy, 2017). It is well known that increase of [Ca2+]i concentration but decrease of intracellular Mg2+ levels induces activation of nitric oxide synthase (NOS) enzyme. By catalytic activity of NOS, nitric oxide synthetizes in neurons. In turn, it induces pain through production of excitatory amino acids and substance P (Medvedeva et al. 2008). Results of recent studies indicated involvement of chemothrepeutic agents (i.e. cisplatin, oxaliplatin and paclitaxel)-induced mitochondrial oxidative stress through activation of Thermo TRP channels such as TRPA1, TRPV1 and TRPM8, although antioxidants induced protective action on the pain induction through inhibition of the TRP channels in the experimental animals (Materazzi et al. 2012). In the oral presentation, I discussed novel effects of chemotherapeutic agents on the peripheral pain by the regulation of TRP channels. I concluded that the chemotherapeutic agents cause TRP channel activation and oxidative stress, which may lead to the pathology of peripheral pain. Itseems to that the exact relationship between TRP channel activation and chemotherapeutic agents still remain to be determined.

Identification and characterization of a novel calmodulin binding site in Drosophila TRP C-terminus

Transient receptor potential (TRP) channels are a group of essential cation channels involved in many important sensory signal transduction processes, such as light, temperature, tastes and pressure sensing. Drosophila TRP channel is the first discovered family member and plays important roles in photo-transduction in Drosophila. Calmodulin (CaM), an important downstream effector of Ca2+ signal, was considered as a vital regulator of TRP activities. In this study, we discovered a novel Ca2+ dependent CaM binding site (TRP 783–862) in between the previously reported two calmodulin binding sites (CBSs). The isothermal titration calorimetry (ITC) and the size exclusion chromatography coupled with multi-angle static light scattering (SEC-MALS) results showed that the dissociation constant (Kd) between TRP 783–862 and Ca2+-CaM is 0.10 ± 0.04 μM and their binding stoichiometry is 1:1. In addition, the shortest Ca2+-CaM interaction region and core CaM binding sequences in TRP 783–862 were dissected by the boundary mapping and mutagenesis experiments. More interestingly, by comparing the circular dichroism (CD) spectra before and after Ca2+-CaM binding, the TRP 783–862 fragment showed Ca2+-CaM binding dependent secondary structure changes, indicating that the interaction between CaM and Drosophila TRP channel may have a conformational impact on TRP structure. In summary, by identifying and characterizing a novel CaM binding site in TRP C-terminus, our findings provided a biochemical and structural basis for further in vivo functional studies of Ca2+-mediated TRP channel regulation through CaM/TRP interaction.

Molecular basis for the sensitivity of TRP channels to polyunsaturated fatty acids

Transient receptor potential (TRP) channels represent a superfamily of unselective cation channels that are subdivided into seven subfamilies based on their sequence homology and differences in gating and functional properties. Little is known about the molecular mechanisms of TRP channel regulation, particularly of the “canonical” TRP (TRPC) subfamily and their activation by polyunsaturated fatty acids (PUFAs). Here, we analyzed the structure-function relationship of Drosophila fruit fly TRPC channels. The primary aim was to uncover the molecular basis of PUFA sensitivity of Drosophila TRP-like (TRPL) and TRPgamma channels. Amino acid (aa) sequence alignment of the three Drosophila TRPC channels revealed 50 aa residues highly conserved in PUFA-sensitive TRPL and TRPgamma channels but not in the PUFA-insensitive TRP channel. Substitution of respective aa in TRPL by corresponding aa of TRP identified 18 residues that are necessary for PUFA-mediated activation of TRPL. Most aa positions are located within a stretch comprising transmembrane domains S2–S4, whereas six aa positions have been assigned to the proximal cytosolic C-terminus. Interestingly, residues I465 and S471 are required for activation by 5,8,11,14-eicosatetraynoic acid (ETYA) but not 5,8,11-eicosatriynoic acid (ETI). As proof of concept, we generated a PUFA-sensitive TRP channel by exchanging the corresponding aa from TRPL to TRP. Our study demonstrates a specific aa pattern in the transmembrane domains S2–S4 and the proximal C-terminus essential for TRP channel activation by PUFAs.

Ca2+ Regulation of TRP Ion Channels.

Ca2+ signaling influences nearly every aspect of cellular life. Transient receptor potential (TRP) ion channels have emerged as cellular sensors for thermal, chemical and mechanical stimuli and are major contributors to Ca2+ signaling, playing an important role in diverse physiological and pathological processes. Notably, TRP ion channels are also one of the major downstream targets of Ca2+ signaling initiated either from TRP channels themselves or from various other sources, such as G-protein coupled receptors, giving rise to feedback regulation. TRP channels therefore function like integrators of Ca2+ signaling. A growing body of research has demonstrated different modes of Ca2+-dependent regulation of TRP ion channels and the underlying mechanisms. However, the precise actions of Ca2+ in the modulation of TRP ion channels remain elusive. Advances in Ca2+ regulation of TRP channels are critical to our understanding of the diversified functions of TRP channels and complex Ca2+ signaling.

Targeting Transient Receptor Potential Channels in Cardiometabolic Diseases and Myocardial Ischemia Reperfusion Injury.

Cardiovascular disease is still the most frequent cause of death in both developed and developing countries while metabolic syndrome and myocardial ischemia reperfusion (I/R) injury are the common risk factors responsible for the impaired cardiac function. Transient receptor potential (TRP) channels are non-selective cation channels, that sense a broad range of stimuli from physical conditions such as stretch, to chemicals including capsaicin. The diverse studies have revealed multifunctional roles of TRP channels in the physiological conditions and various diseases while some members of TRP channel superfamily are demonstrated to participate in the pathophysiology of cardiometabolic diseases and myocardial ischemia reperfusion injury. Here we discuss the roles of TRP channels in myocardial ischemia reperfusion and cardiometabolic diseases and their potential use in treating these diseases. Regulation of TRP channels facilitates the control of metabolic syndrome such as obesity, diabetes mellitus, hypertension, and atherosclerosis. This review presents an overview of our current knowledge regarding the physiological functions of TRP channels in the metabolic and cardiovascular systems and their contributions to cardiometabolic diseases and I/R injury. On the basis of these discoveries, the therapeutic potential of targeting novel TRP channels can be proposed for the treatment of cardiometabolic diseases and I/R injury.

MicroRNA-135a is involved in podocyte injury in a transient receptor potential channel 1-dependent manner.

Transient receptor potential (TRP) cation channels are essential for normal cellular physiology, and their abnormal expression may lead to a number of disorders, including podocytopathy. Therefore, it is crucial to understand the mechanisms underlying the regulation of TRP channels. In the present study, microRNA (miR)-135a was found to be upregulated in patients with focal segmental glomerulosclerosis and mice treated with adriamycin (ADR). In cultured podocytes, transforming growth factor (TGF)-β and ADR were found to promote miR-135a expression. Conversely, TRP channel 1 (TRPC1) protein levels were markedly downregulated in podocytes from mice treated with ADR, as well as in cultured podocytes treated with ADR and TGF-β. Ectopic expression of miR-135a led to severe podocyte injury and disarray of the podocyte cytoskeleton, whereas podocyte-specific expression of TRPC1 was able to reverse the pathological effects of miR-135a in cultured podocytes. Moreover, using Luciferase reporter assays and western blot analysis, TRPC1 was identified as a target gene of miR-135a. To the best of our knowledge, this is the first study to demonstrate the role of TRPC1 in the development of podocyte injury and disorders of the podocyte cytoskeleton, which may contribute to the development of novel therapeutics for podocyte injury-associated kidney diseases.

TNF-α–Induced p38MAPK Activation Regulates TRPA1 and TRPV4 Activity in Odontoblast-Like Cells

The transient receptor potential (TRP) channels are unique cellular sensors that are widely expressed in many neuronal and nonneuronal cells. Among the TRP family members, TRPA1 and TRPV4 are emerging as candidate mechanosensitive channels that play a pivotal role in inflammatory pain and mechanical hyperalgesia. Odontoblasts are nonneuronal cells that possess many of the features of mechanosensitive cells and mediate important defense and sensory functions. However, the effect of inflammation on the activity of the odontoblast's mechanosensitive channels remains unknown. By using immunohistochemistry and calcium microfluorimetry, we showed that odontoblast-like cells express TRPA1 and TRPV4 and that these channels were activated by hypotonicity-induced membrane stretch. Short treatment of odontoblast-like cells with tumor necrosis factor (TNF)-α enhanced TRPA1 and TRPV4 responses to their chemical agonists and membrane stretch. This enhanced channel activity was accompanied by phospho-p38 mitogen-activated protein kinase (MAPK) expression. Treatment of cells with the p38 inhibitor SB202190 reduced TNF-α effects, suggesting modulation of channel activity via p38 MAPK. In addition, TNF-α treatment also resulted in an up-regulation of TRPA1 expression but down-regulation of TRPV4. Unlike TRPV4, enhanced TRPA1 expression was also evident in dental pulp of carious compared with noncarious teeth. SB202190 treatment significantly reduced TNF-α-induced TRPA1 expression, suggesting a role for p38 MAPK signaling in modulating both the transcriptional and non-transcriptional regulation of TRP channels in odontoblasts.

Polycystin-2 (TRPP2) Regulation by Ca2+ Is Effected and Diversified by Actin-Binding Proteins

Calcium regulation of Ca2+-permeable ion channels is an important mechanism in the control of cell function. Polycystin-2 (PC2, TRPP2), a member of the transient receptor potential superfamily, is a nonselective cation channel with Ca2+ permeability. The molecular mechanisms associated with PC2 regulation by Ca2+ remain ill-defined. We recently demonstrated that PC2 from human syncytiotrophoblast (PC2hst) but not the in vitro translated protein (PC2iv), functionally responds to changes in intracellular (cis) Ca2+. In this study we determined the regulatory effect(s) of Ca2+-sensitive and -insensitive actin-binding proteins (ABPs) on PC2iv channel function in a lipid bilayer system. The actin-bundling protein α-actinin increased PC2iv channel function in the presence of cis Ca2+, although instead was inhibitory in its absence. Conversely, filamin that shares actin-binding domains with α-actinin had a strong inhibitory effect on PC2iv channel function in the presence, but no effect in the absence of cis Ca2+. Gelsolin stimulated PC2iv channel function in the presence, but not the absence of cis Ca2+. In contrast, profilin that shares actin-binding domains with gelsolin, significantly increased PC2iv channel function both in the presence and absence of Ca2+. The distinct effect(s) of the ABPs on PC2iv channel function demonstrate that Ca2+ regulation of PC2 is actually mediated by direct interaction(s) with structural elements of the actin cytoskeleton. These data indicate that specific ABP-PC2 complexes would confer distinct Ca2+-sensitive properties to the channel providing functional diversity to the cytoskeletal control of transient receptor potential channel regulation.

Phosphoinositide regulation of TRP channels.

Transient Receptor Potential (TRP) channels are activated by stimuli as diverse as heat, cold, noxious chemicals, mechanical forces, hormones, neurotransmitters, spices, and voltage. Besides their presumably similar general architecture, probably the only common factor regulating them is phosphoinositides. The regulation of TRP channels by phosphoinositides is complex. There are a large number of TRP channels where phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2 or PIP2] acts as a positive cofactor, similarly to many other ion channels. In several cases, however, PI(4,5)P2 inhibits TRP channel activity, sometimes even concurrently with the activating effect. This chapter will provide a comprehensive overview of the literature on regulation of TRP channels by membrane phosphoinositides.

Regulation of transient receptor potential channels by the phospholipase C pathway.

Transient Receptor Potential (TRP) channels were discovered while analyzing visual mutants in Drosophila. The protein encoded by the transient receptor potential (trp) gene is a Ca(2+) permeable cation channel activated downstream of the phospholipase C (PLC) pathway. While searching for homologs in other organisms, a surprisingly large number of mammalian TRP channels was cloned. The regulation of TRP channels is quite diverse, but many of them are either activated downstream of PLC, or modulated by it. This review will summarize the current knowledge on regulation of TRP channels by PLC, with special focus on TRPC-s, which can be considered as effectors of PLC and the heat- and capsaicin-sensitive TRPV1, which is modulated by the PLC pathway in a complex manner.

Mutation of Light-dependent Phosphorylation Sites of the Drosophila Transient Receptor Potential-like (TRPL) Ion Channel Affects Its Subcellular Localization and Stability

The Drosophila phototransduction cascade terminates in the opening of the ion channel transient receptor potential (TRP) and TRP-like (TRPL). Contrary to TRP, TRPL undergoes light-dependent subcellular trafficking between rhabdomeric photoreceptor membranes and an intracellular storage compartment, resulting in long term light adaptation. Here, we identified in vivo phosphorylation sites of TRPL that affect TRPL stability and localization. Quantitative mass spectrometry revealed a light-dependent change in the TRPL phosphorylation pattern. Mutation of eight C-terminal phosphorylation sites neither affected multimerization of the channels nor the electrophysiological response of flies expressing the mutated channels. However, these mutations resulted in mislocalization and enhanced degradation of TRPL after prolonged dark-adaptation. Mutation of subsets of the eight C-terminal phosphorylation sites also led to a reduction of TRPL content and partial mislocalization in the dark. This suggests that a light-dependent switch in the phosphorylation pattern of the TRPL channel mediates stable expression of TRPL in the rhabdomeres upon prolonged dark-adaptation.

Distribution and Expression of Non-Neuronal Transient Receptor Potential (TRPV) Ion Channels in Rosacea

Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.