Showing papers on "TRPV published in 2021"

Trpv protein family—from mechanosensing to cancer invasion

Abstract: Biophysical cues from the cellular microenvironment are detected by mechanosensitive machineries that translate physical signals into biochemical signaling cascades. At the crossroads of extracellular space and cell interior are located several ion channel families, including TRP family proteins, that are triggered by mechanical stimuli and drive intracellular signaling pathways through spatio-temporally controlled Ca2+-influx. Mechanosensitive Ca2+-channels, therefore, act as critical components in the rapid transmission of physical signals into biologically compatible information to impact crucial processes during development, morphogenesis and regeneration. Given the mechanosensitive nature of many of the TRP family channels, they must also respond to the biophysical changes along the development of several pathophysiological conditions and have also been linked to cancer progression. In this review, we will focus on the TRPV, vanilloid family of TRP proteins, and their connection to cancer progression through their mechanosensitive nature.

Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation

Abstract: Transient receptor potential vanilloid (TRPV) channels are part of the TRP channel superfamily and named after the first identified member TRPV1, that is sensitive to the vanillylamide capsaicin. Their overall structure is similar to the structure of voltage gated potassium channels (Kv) built up as homotetramers from subunits with six transmembrane helices (S1-S6). Six TRPV channel subtypes (TRPV1-6) are known, that can be subdivided into the thermoTRPV (TRPV1-4) and the Ca2+-selective TRPV channels (TRPV5, TRPV6). Contrary to Kv channels, TRPV channels are not primary voltage gated. All six channels have distinct properties and react to several endogenous ligands as well as different gating stimuli such as heat, pH, mechanical stress, or osmotic changes. Their physiological functions are highly diverse and subtype as well as tissue specific. In many tissues they serve as sensors for different pain stimuli (heat, pressure, pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions and the development of macrophages. Due to their fundamental role in manifold physiological and pathophysiological processes, TRPV channels are promising targets for drug development. However, drugs targeting specific TRPV channels, that are suitable for drug therapy, are rare. Moreover, selective and potent compounds for further research at TRPV channels are often lacking. In this review different aspects of the structure, the different gating stimuli, the expression pattern, the physiological and pathophysiological roles as well as the modulating mechanisms of synthetic, natural and endogenous ligands are summarized.

Vascular Dysfunction in Diabetes and Obesity: Focus on TRP Channels.

Abstract: Transient receptor potential (TRP) superfamily consists of a diverse group of non-selective cation channels that has a wide tissue distribution and is involved in many physiological processes including sensory perception, secretion of hormones, vasoconstriction/vasorelaxation, and cell cycle modulation. In the blood vessels, TRP channels are present in endothelial cells, vascular smooth muscle cells, perivascular adipose tissue (PVAT) and perivascular sensory nerves, and these channels have been implicated in the regulation of vascular tone, vascular cell proliferation, vascular wall permeability and angiogenesis. Additionally, dysfunction of TRP channels is associated with cardiometabolic diseases, such as diabetes and obesity. Unfortunately, the prevalence of diabetes and obesity is rising worldwide, becoming an important public health problems. These conditions have been associated, highlighting that obesity is a risk factor for type 2 diabetes. As well, both cardiometabolic diseases have been linked to a common disorder, vascular dysfunction. In this review, we briefly consider general aspects of TRP channels, and we focus the attention on TRPC (canonical or classical), TRPV (vanilloid), TRPM (melastatin), and TRPML (mucolipin), which were shown to be involved in vascular alterations of diabetes and obesity or are potentially linked to vascular dysfunction. Therefore, elucidation of the functional and molecular mechanisms underlying the role of TRP channels in vascular dysfunction in diabetes and obesity is important for the prevention of vascular complications and end-organ damage, providing a further therapeutic target in the treatment of these metabolic diseases.

Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia.

Abstract: Background & Aims Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been investigated systematically. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has not been assessed. Methods Duodenal biopsy specimens from FD and control subjects, and peroxisome proliferator-activated receptor-α (PPARα) null mice were cultured at a pH of 3.0 and 7.4. Mast cell (MC) number, the release of their mediators, and the expression of transient receptor potential vanilloid receptor (TRPV)1 and TRPV4, were evaluated. All measurements also were performed in the presence of a selective blocker of neuronal action potential (tetradotoxin). FD and control biopsy specimens in acidified medium also were incubated in the presence of different PEA concentrations, alone or combined with a selective PPARα or PPAR-γ antagonist. Results An acid-induced increase in MC density and the release of their mediators were observed in both dyspeptic patients and controls; however, this response was amplified significantly in FD. This effect was mediated by submucosal nerve fibers and up-regulation of TRPV1 and TRPV4 receptors because pretreatment with tetradotoxin significantly reduced MC infiltration. The acid-induced endogenous release of PEA was impaired in FD and its exogenous administration counteracts MC activation and TRPV up-regulation. Conclusions Duodenal acid exposure initiates a cascade of neuronal-mediated events culminating in MC activation and TRPV overexpression. These phenomena are consequences of an impaired release of endogenous PEA. PEA might be regarded as an attractive therapeutic strategy for the treatment of FD.

The role of TRPV channels in osteoporosis.

Abstract: As the world's population ages, the treatment of osteoporosis is a major problem to be addressed. The cause of osteoporosis remains unclear. Ca2+ is not only an important component of bones but also plays a key role in osteoporosis treatment. Transient receptor potential vanilloid (TRPV) channels are one of the TRP channel families that is widely distributed in various organs, playing an important role in the physiological regulation of the human body. Bone formation and bone absorption may require Ca2+ transport via TRPV channels. It has been proven that the TRPV subtypes 1, 2, 4, 5, 6 (TRPV1, TRPV2, TRPV4, TRPV5, TRPV6) may affect bone metabolism balance through selective regulation of Ca2+. They significantly regulate osteoblast/osteoclast proliferation, differentiation and function. The purpose of this review is to explore the mechanisms of TRPV channels involved in regulation of the differentiation of osteoblasts and osteoclasts, as well as to discuss the latest developments in current researches, which may provide new clues and directions for an in-depth study of osteoporosis and other related bone metabolic diseases.

TRP channels in health and disease at a glance.

Abstract: The transient receptor potential (TRP) channel superfamily consists of a large group of non-selective cation channels that serve as cellular sensors for a wide spectrum of physical and environmental stimuli. The 28 mammalian TRPs, categorized into six subfamilies, including TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin) and TRPP (polycystin), are widely expressed in different cells and tissues. TRPs exhibit a variety of unique features that not only distinguish them from other superfamilies of ion channels, but also confer diverse physiological functions. Located at the plasma membrane or in the membranes of intracellular organelles, TRPs are the cellular safeguards that sense various cell stresses and environmental stimuli and translate this information into responses at the organismal level. Loss- or gain-of-function mutations of TRPs cause inherited diseases and pathologies in different physiological systems, whereas up- or down-regulation of TRPs is associated with acquired human disorders. In this Cell Science at a Glance article and the accompanying poster, we briefly summarize the history of the discovery of TRPs, their unique features, recent advances in the understanding of TRP activation mechanisms, the structural basis of TRP Ca2+ selectivity and ligand binding, as well as potential roles in mammalian physiology and pathology.

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid accelerates the healing of colitis by inhibiting transient receptor potential vanilloid 4-mediated signaling

Abstract: 5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE) is an eicosapentaenoic acid-derived lipid metabolite, which we previously detected in inflamed mouse colon. In this study, we investigated the pathophysiological roles of 5,6-DiHETE in murine colitis and its underlying mechanisms of action, focusing on the effects on transient receptor potential vanilloid (TRPV) channel activity. Oral administration of dextran sodium sulfate (DSS, 2%, for 4 days) caused colon inflammation, which peaked on day 7 and gradually declined by day 18. 5,6-DiHETE concentration in colon tissue was significantly increased during the healing phase of colitis (days 9 to 18). In vitro study showed that pretreatment with 5,6-DiHETE (0.1-1 μM, 30 minutes) significantly inhibited endothelial barrier disruption induced by a TRPV4 agonist (GSK1016790A, 50 nM). Intracellular Ca2+ imaging also showed that pretreatment with 5,6-DiHETE (1 μM, 10 minutes) reduced GSK1016790A-induced intracellular Ca2+ increase in HEK293T cells overexpressing TRPV4. In vivo, intraperitoneal administration of 5,6-DiHETE (50 µg kg-1 day-1 ) during the healing phase accelerated the recovery from DSS-induced colitis. Pathological studies showed that the administration of 5,6-DiHETE inhibited edema formation and leukocyte infiltration in inflamed colon tissue. In conclusion, we identified 5,6-DiHETE as a novel endogenous TRPV4 antagonist, and we also demonstrated that its administration promotes the healing of colitis by inhibiting inflammatory responses.

Regulation of the Membrane Trafficking of the Mechanosensitive Ion Channels TRPV1 and TRPV4 by Zonular Tension, Osmotic Stress and Activators in the Mouse Lens

Abstract: Lens water transport generates a hydrostatic pressure gradient that is regulated by a dual-feedback system that utilizes the mechanosensitive transient receptor potential vanilloid (TRPV) channels, TRPV1 and TRPV4, to sense changes in mechanical tension and extracellular osmolarity. Here, we investigate whether the modulation of TRPV1 or TRPV4 activity dynamically affects their membrane trafficking. Mouse lenses were incubated in either pilocarpine or tropicamide to alter zonular tension, exposed to osmotic stress, or the TRPV1 and TRPV4 activators capsaicin andGSK1016790A (GSK101), and the effect on the TRPV1 and TRPV4 membrane trafficking in peripheral fiber cells visualized using confocal microscopy. Decreases in zonular tension caused the removal of TRPV4 from the membrane of peripheral fiber cells. Hypotonic challenge had no effect on TRPV1, but increased the membrane localization of TRPV4. Hypertonic challenge caused the insertion of TRPV1 and the removal of TRPV4 from the membranes of peripheral fiber cells. Capsaicin caused an increase in TRPV4 membrane localization, but had no effect on TRPV1; while GSK101 decreased the membrane localization of TRPV4 and increased the membrane localization of TRPV1. These reciprocal changes in TRPV1/4 membrane localization are consistent with the channels acting as mechanosensitive transducers of a dual-feedback pathway that regulates lens water transport.

Smaller bladder capacity and stronger bladder contractility in patients with ketamine cystitis are associated with elevated TRPV1 and TRPV4.

Abstract: Stronger contractility and smaller bladder capacity are common symptoms in ketamine cystitis (KC). This study investigates the association between expression levels of transient receptor potential cation channel subfamily V (TRPV) proteins and the clinical characteristics of KC. Bladder tissues were obtained from 24 patients with KC and four asymptomatic control subjects. Video urodynamic parameters were obtained before surgical procedures. The TRPV proteins were investigated by immunoblotting, immunofluorescence staining, and immunohistochemistry. The Pearson test was used to associate the expression levels of TRPV proteins with clinical characteristics of KC. The expression level of TRPV1 and TRPV4 was significantly higher in the severe KC bladders than in mild KC or control bladders. The TRPV1 proteins were localized in all urothelial cell layers, and TRPV4 was located in the basal cells and lamina propria. The expression of TRPV1 was negatively associated with maximal bladder capacity (r = − 0.66, P = 0.01). The expression of TRPV4 was positively associated with the velocity of detrusor pressure rise to the maximum flow rate (r = 0.53, P = 0.01). These observations suggest smaller bladder capacity and stronger contractility in KC are associated with an elevated expression of TRPV1 and TRPV4, respectively.

Prodromal sensory neuropathy in Pink1 -/- SNCA A53T double mutant Parkinson mice.

Abstract: Aims Parkinson's Disease (PD) is frequently associated with a prodromal sensory neuropathy manifesting with sensory loss and chronic pain. We have recently shown that PD-associated sensory neuropathy in patients is associated with high levels of glucosylceramides. Here, we assessed the underlying pathology and mechanisms in Pink1-/- SNCAA53T double mutant mice. Methods We studied nociceptive and olfactory behaviour and the neuropathology of dorsal root ganglia (DRGs), including ultrastructure, mitochondrial respiration, transcriptomes, outgrowth and calcium currents of primary neurons, and tissue ceramides and sphingolipids before the onset of a PD-like disease that spontaneously develops in Pink1-/- SNCAA53T double mutant mice after 15 months of age. Results Similar to PD patients, Pink1-/- SNCAA53T mice developed a progressive prodromal sensory neuropathy with a loss of thermal sensitivity starting as early as four months of age. In analogy to human plasma, lipid analyses revealed an accumulation of glucosylceramides (GlcCer) in the DRGs and sciatic nerves, which was associated with pathologic mitochondria, impairment of mitochondrial respiration, and deregulation of transient receptor potential and TRPV and TRPA channels at mRNA, protein and functional levels in DRGs. Direct exposure of DRG neurons to GlcCer caused transient hyperexcitability, followed by a premature decline of the viability of sensory neurons cultures upon repeated GlcCer application. Conclusions The results suggest that pathological GlcCer contribute to prodromal sensory disease in PD mice via mitochondrial damage and calcium channel hyperexcitability. GlcCer-associated sensory neuron pathology might be amenable to GlcCer lowering therapeutic strategies.

Effects of Hyperthermia on TRPV1 and TRPV4 Channels Expression and Oxidative Markers in Mouse Brain.

Abstract: Heat stress increases the core body temperature through the pathogenic process. The pathogenic process leads to the release of free radicals, such as superoxide production. Heat stress in the central nervous system (CNS) can cause neuronal damage and symptoms such as delirium, coma, and convulsion. TRPV1 (Transient Receptor Potential Vanilloid1) and TRPV4 genes are members of the TRPV family, including integral membrane proteins that act as calcium-permeable channels. These channels act as thermosensors and have essential roles in the cellular regulation of heat responses. The objective of this study is to examine the effect of general heat stress on the expression of TRPV1 and TRPV4 channels. Furthermore, oxidative markers were measured in the brain of the same heat-stressed mice. Our results show that heat stress leads to a significant upregulation of TRPV1 expression within 21–42 days, while TRPV4 expression decreased significantly in a time-dependent manner. Alterations in the oxidative markers were also observed in the heat-stressed mice.

Role of Known Transient Receptor Potential Vanilloid Channels in Modulating Cardiac Mechanobiology

Abstract: The Transient Receptor Potential (TRP) channels have been described in almost every mammalian cell type. Several members of the Vanilloid (TRPV) subtype have been found to play important roles in modulating cardiac function through calcium handling and structure under both physiologic and pathologic conditions in their response to systemic and local mechanobiological cues. In this review we will consider the most studied TRPV channels in the cardiovascular field; TRPV1 as a modulator of cardiac hypertrophy; TRPV2 as a structural and functional protein; TRPV3 in the development of hypertrophy and myocardial fibrosis; and TRPV4 in its roles modulating the fibrotic and functional responses of the heart to pressure overload. Lastly, we will also review the potential overlapping roles of these channels with other TRP proteins as well as the advances in translational and clinical arenas associated with TRPV channels.

Effect of Alpha-Glucosyl-Hesperidin Consumption on Lens Sclerosis and Presbyopia

Abstract: Presbyopia is characterized by a decline in the ability to accommodate the lens. The most commonly accepted theory for the onset of presbyopia is an age-related increase in the stiffness of the lens. However, the cause of lens sclerosis remains unclear. With age, water microcirculation in the lens could change because of an increase in intracellular pressure. In the lens, the intracellular pressure is controlled by the Transient Receptor Potential Vanilloid (TRPV) 1 and TRPV4 feedback pathways. In this study, we tried to elucidate that administration of α-glucosyl-hesperidin (G-Hsd), previously reported to prevent nuclear cataract formation, affects lens elasticity and the distribution of TRPV channels and Aquaporin (AQP) channels to meet the requirement of intracellular pressure. As a result, the mouse control lens was significantly toughened compared to both the 1% and 2% G-Hsd mouse lens treatments. The anti-oxidant levels in the lens and plasma decreased with age; however, this decrease could be nullified with either 1% or 2% G-Hsd treatment in a concentration- and exposure time-dependent manner. Moreover, G-Hsd treatment affected the TRPV4 distribution, but not TRPV1, AQP0, and AQP5, in the peripheral area and could maintain intracellular pressure. These findings suggest that G-Hsd has great potential as a compound to prevent presbyopia and/or cataract formation.

Activation of TRPV4 channels leads to a consistent tocolytic effect on human myometrial tissues.

Abstract: Background Human myometrium is a therapeutic target for labor induction and preterm labor. Objective This study aimed to assess the physiological role of alternative calcium conductance on contractions triggered by uterotonic drugs in human myometrium. Membrane conductances, supported by TRPV channels, may provide alternative pathways to control either free intracellular and/or submembrane Ca2+-concentration, which in turn will modulate membrane polarization and contractile responses. Study design Uterine biopsies were obtained from consenting women undergoing elective caesarean delivery at term without labor (N = 22). Isometric tension measurements were performed on uterine smooth muscle strips (n = 132). Amplitude, frequency, and area under the curve (AUC) of phasic contractions, as well as resting tone, were measured under various experimental conditions. Immuno histo- and cyto-chemistry, as well as Western blot analyses, have been performed with specific antibodies against TRPV1, TRPV3, and TRPV4 proteins. TRPV4 agonists; GSK1016790A, 4αPDD, and 5,6-EET were used to assess the role of TRPV4 channels on rhythmic activity triggered by 30–300 nM oxytocin. 5 μM of ruthenium red was used as an efficient blocker of ionic current through TRPV4 channels. Nanomolar concentrations of iberiotoxin (IbTX) were also used to confirm the downstream involvement of BKCa channels in controlling uterine reactivity and contractility. Results The expression of TRPV3 and TRPV4 isoforms has now been demonstrated in human myometrial tissue and cell culture. Nanomolar concentrations of the TRPV4 agonists, (either GSK1016790A or 4αPDD) abolished the rhythmic contractions, resulting in a rapid and consistent tocolytic effect. While 5 μM of ruthenium reversed this tocolytic effect. The addition of IbTX (a BKCa channel blocker) reversed the effects of GSK1016790A. Carvacrol, a TRPV3 agonist, had similar tocolytic effects on rhythmic contractions albeit at higher concentrations. This inhibitory effect was also reversed by ruthenium red. Conclusion Collectively, these data suggest that activation of TRPV4 leads to a Ca2+ entry and subsequent BKCa channel activation (increase in open state probability), which in turn hyperpolarizes the myometrial cell membrane, inactivating L-type Ca2+ channels and efficiently abrogates contractile activity. Consequently, alternative Ca2+ conductance supported by TRPV4 plays a physiological role in the modulation of myometrial reactivity.

Transient Receptor Potential Vanilloid Subtype 1: Potential Role in Infection, Susceptibility, Symptoms and Treatment of COVID-19.

Abstract: The battle against the new coronavirus that continues to kill millions of people will be still long. Novel strategies are demanded to control infection, mitigate symptoms and treatment of COVID-19. This is even more imperative given the long sequels that the disease has on the health of the infected. The discovery that S protein includes two ankyrin binding motifs (S-ARBMs) and that the transient receptor potential vanilloid subtype 1 (TRPV-1) cation channels contain these ankyrin repeat domains (TRPs-ARDs) suggest that TRPV-1, the most studied member of the TRPV channel family, can play a role in binding SARS-CoV-2. This hypothesis is strengthened by studies showing that other respiratory viruses bind the TRPV-1 on sensory nerves and epithelial cells in the airways. Furthermore, the pathophysiology in COVID-19 patients is similar to the effects generated by TRPV-1 stimulation. Lastly, treatment with agonists that down-regulate or inactivate TRPV-1 can have a beneficial action on impaired lung functions and clearance of infection. In this review, we explore the role of the TRPV-1 channel in the infection, susceptibility, pathogenesis, and treatment of COVID-19, with the aim of looking at novel strategies to control infection and mitigate symptoms, and trying to translate this knowledge into new preventive and therapeutic interventions.

Expression of transient receptor potential vanilloid genes and proteins in diabetic rat heart.

Abstract: Cardiac complications are leading causes of death in diabetic patients. Imbalance of Ca2+ homeostasis is a hallmark of cardiac dysfunction in diabetes, while TRPV channels are non-selective for cations and are permeable to Ca2+. Our aim was to evaluate the expression levels of TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 genes and proteins in cardiac tissue at 3 days and 4, 8, and 12 weeks after induction of diabetes. Sprague-Dawley rats were assigned to control and DM groups. DM was induced by intraperitoneal injection of streptozotocin (60 mg/kg). The expression levels of TRPV genes were analyzed by the quantitative reverse transcription polymerase chain reaction, and TRPV proteins were determined by western blotting. Compared to controls, the expression levels of TRPV2, TRPV3, and TRPV6 in diabetic myocardium did not change, while TRPV1 decreased at 4, 8, and 12 weeks, TRPV4 was upregulated at 3 days and 4, 8, and 12 weeks, TRPV5 mRNA increased at 8 and 12 weeks, and TRPV5 protein increased at 4, 8, and 12 weeks. Our findings showed that TRPV1, TRPV4, and TRPV5 are associated with the diabetic heart.

TRPV2 channel-based therapies in the cardiovascular field. Molecular underpinnings of clinically relevant therapies

Abstract: The transient receptor potential (TRP) ion channel family is composed of twenty-seven channel proteins that are ubiquitously expressed in the human body The TRPV (vanilloid) subfamily has been a recent target of investigation within the cardiovascular field TRPV1, which is sensitive to heat as well as vanilloids, is the best characterized TRPV channel and is the namesake for the subfamily that includes six members Research into the function of TRPV2 has suggested that it plays an important role in cardiovascular function Over the last twenty years a greater understanding of the differences among the TRPV channels has allowed for more precise experimentation and has opened various translational opportunities TRPV2 has been found to be a both a mechanosensor and a mediator of calcium handling and has been found to play important roles in healthy and diseased cardiomyocytes These roles have been translated into clinical studies in patients with muscular dystrophy (both agonism and antagonism) as well as in patients with cardiomyopathy and heart failure with reduced ejection fraction Its role as a structural protein has also been elucidated, though the clinical significance of this finding has yet to be established Despite the clinical progress that has been made there is still a need for large, prospective randomized studies with TRPV2 channel agonists and antagonists in order to bring these basic and translational science findings to the bedside

TRPV4-Mediated Epithelial Junction Disruption in Allergic Rhinitis Triggered by House Dust Mites:

Abstract: BackgroundEpithelial barrier disruption is a crucial feature of allergic rhinitis (AR). Previous reports have indicated the role of transient receptor potential vanilloid (TRPV) 4 in regulating the...

Advancement in research on the role of the transient receptor potential vanilloid channel in cerebral ischemic injury (Review).

Abstract: Stroke is a common critical disease occurring in middle-aged and elderly individuals, and is characterized by high morbidity, lethality and mortality. As such, it is of great concern to medical professionals. The aim of the present review was to investigate the effects of transient receptor potential vanilloid (TRPV) subtypes during cerebral ischemia in ischemia-reperfusion animal models, oxygen glucose deprivation and in other administration cell models in vitro to explore new avenues for stroke research and clinical treatments. TRPV1, TRPV2 and TRPV4 employ different methodologies by which they confer protection against cerebral ischemic injury. TRPV1 and TRPV4 are likely related to the inhibition of inflammatory reactions, neurotoxicity and cell apoptosis, thus promoting nerve growth and regulation of intracellular calcium ions (Ca2+). The mechanisms of neuroprotection of TRPV1 are the JNK pathway, N-methyl-D-aspartate (NMDA) receptor and therapeutic hypothermia. The mechanisms of neuroprotection of TRPV4 are the PI3K/Akt pathways, NMDA receptor and p38 MAPK pathway, amongst others. The mechanisms by which TRPV2 confers its protective effects are predominantly connected with the regulation of nerve growth factor, MAPK and JNK pathways, as well as JNK-dependent pathways. Thus, TRPVs have the potential for improving outcomes associated with cerebral ischemic or reperfusion injuries. The protection conferred by TRPV1 and TRPV4 is closely related to cellular Ca2+ influx, while TRPV2 has a different target and mode of action, possibly due to its expression sites. However, in light of certain contradictory research conclusions, further experimentation is required to clarify the mechanisms and specific pathways by which TRPVs act to alleviate nerve injuries.

Nanchung and Inactive define pore properties of the native auditory transduction channel in Drosophila.

Abstract: Auditory transduction is mediated by chordotonal (Cho) neurons in Drosophila larvae, but the molecular identity of the mechanotransduction (MET) channel is elusive. Here, we established a whole-cell recording system of Cho neurons and showed that two transient receptor potential vanilloid (TRPV) channels, Nanchung (NAN) and Inactive (IAV), are essential for MET currents in Cho neurons. NAN and IAV form active ion channels when expressed simultaneously in S2 cells. Point mutations in the pore region of NAN-IAV change the reversal potential of the MET currents. Particularly, residues 857 through 990 in the IAV carboxyl terminus regulate the kinetics of MET currents in Cho neurons. In addition, TRPN channel NompC contributes to the adaptation of auditory transduction currents independent of its ion-conduction function. These results indicate that NAN-IAV, rather than NompC, functions as essential pore-forming subunits of the native auditory transduction channel in Drosophila and provide insights into the gating mechanism of MET currents in Cho neurons.

Modern concepts of the role of transient receptor potential channel vanilloid subfamily (TRPV) in development osmotic airway hyperresponsiveness in asthma patients (review)

Abstract: Introduction. Airway hyperresponsiveness to osmotic stimuli is often found among patients with asthma. It is assumed that the transient receptor potential channels of vanilloid subfamily (TRPV) may play a key role in the onset of this phenomenon.Aim. Review of modern world literature data on osmotic airway hyperresponsiveness and the role of TRPV channels in its development.Materials and methods. This review summarizes the data from articles published over the past five years found in PubMed and Google Scholar. However, earlier publications were also included if necessary.Results. The influence of natural osmotic triggers on the formation of bronchoconstriction in patients with asthma has been demonstrated. The effects that occur in the airways, depending on the functional state of TRPV1, TRPV2 and TRPV4 osmosensitive receptors are described, and the mechanisms that mediate the development of bronchial hyperresponsiveness with the participation of these channels are partially disclosed.Conclusion. It is safe to assume that TRPV channels are directly or indirectly associated with airway hyperresponsiveness to osmotic stimuli. Signaling cascades triggered by TRPV activation largely explain the effects of osmotic influence on the airways and the occurrence of bronchoconstriction. It could be suggested that TRPV1 signaling mediates the development of bronchospasm to hyperosmolar stimuli, while TRPV2 and TRPV4 are most likely involved in hypoosmotic-induced bronchoconstriction. Further study of the role of TRPV1, TRPV2 and TRPV4 in osmotic airway hyperresponsiveness is relevant and promising in terms of pharmacological management of this condition.

Endothelin-1 potentiates TRPV1-mediated vasoconstriction of human adipose arterioles in a protein kinase C-dependent manner.

Abstract: Background and purpose Vascular transient receptor potential vanilloid (TRPV) channels have emerged as important regulators of vascular tone. TRPV1 and endothelin-1 (ET-1) are independently associated with the pathophysiology of coronary vasospasm but the relationship between their vasomotor functions remains unclear. We characterized the vasomotor function of TRPV1 channels in human arterioles and investigated regulation of their vasomotor function by ET-1. Experimental approach Arterioles were threaded on two metal wires, equilibrated in a physiological buffer at 37 o C and exposed to increasing concentrations of capsaicin in the absence or presence of SB366791 (TRPV1-selective inhibitor) or GF109203X (protein kinase C (PKC)-selective inhibitor). Some arterioles were preconstricted with ET-1 or phenylephrine or high potassium buffer. TRPV1 mRNA and protein expression in human arteries were also assessed. Key results TRPV1 transcripts and proteins were detected in human resistance arteries. Capsaicin (1 μM) induced concentration-dependent constriction of endothelium-intact (35 ± 8 % of maximal contraction) and endothelium-denuded (43 ± 11 %) human adipose arterioles (HAA), which was significantly inhibited by SB366791 (0.2 ± 0.1 %). Preconstriction of HAA with ET-1, but not high potassium buffer or phenylephrine, significantly potentiated capsaicin (0.1 μM)-induced constriction (33 ± 7 % vs 12 ± 8 %). GF109203X significantly inhibited potentiation of capsaicin-induced constriction by ET-1. Conclusion and implications TRPV1 channels are expressed in the human vasculature and can influence vascular tone of human arterioles upon activation. Their vasomotor function is modulated by ET-1, mediated in part by PKC. These findings reveal a novel interplay between ET-1 signaling and TRPV1 channels in human VSMC, adding to our understanding of the ion channel mechanisms that regulate human arteriolar tone and may also contribute to the pathophysiology of coronary vasospasm.

Transient Receptor Potential Vanilloid in the Brain Gliovascular Unit: Prospective Targets in Therapy.

Abstract: The gliovascular unit (GVU) is composed of the brain microvascular endothelial cells forming blood-brain barrier and the neighboring surrounding "mural" cells (e.g., pericytes) and astrocytes. Modulation of the GVU/BBB features could be observed in a variety of vascular, immunologic, neuro-psychiatric diseases, and cancers, which can disrupt the brain homeostasis. Ca2+ dynamics have been regarded as a major factor in determining BBB/GVU properties, and previous studies have demonstrated the role of transient receptor potential vanilloid (TRPV) channels in modulating Ca2+ and BBB/GVU properties. The physiological role of thermosensitive TRPV channels in the BBB/GVU, as well as their possible therapeutic potential as targets in treating brain diseases via preserving the BBB are reviewed. TRPV2 and TRPV4 are the most abundant isoforms in the human BBB, and TRPV2 was evidenced to play a main role in regulating human BBB integrity. Interspecies differences in TRPV2 and TRPV4 BBB expression complicate further preclinical validation. More studies are still needed to better establish the physiopathological TRPV roles such as in astrocytes, vascular smooth muscle cells, and pericytes. The effect of the chronic TRPV modulation should also deserve further studies to evaluate their benefit and innocuity in vivo.