TRPV1 from the TRP family: Structure, function, implication in autoimmune diseases and potential therapies

The transient receptor potential vanilloid type 1 (TRPV1) is a non‐selective ion channel that belongs to the TRP family of channels that are activated by vanilloid molecules, including capsaicin. The cloned TRPV1 is a thermosensor, gated by temperature (43–52°C) and low pH. Additional putative endogenous activators of the TRPV1 are the cannabinoid receptor agonist, anandamide, N‐arachydonoil‐dopamine and certain lipoxigenase metabolites of arachidonic acid, as 12‐HPETE and LTB4. The TRPV1 is expressed selectively in a subpopulation of primary sensory neurons with C‐ and A‐delta fibres which also express NGF receptors, the neuropeptides, substance P (SP), neurokinin A and calcitonin gene‐related peptide (CGRP). These neurons being activated by different sensory (mechanichal, thermal and chemical) modalities are defined as polymodal nociceptors, and the peptides released from their peripheral terminals cause neurogenic inflammation. TRPV1 seems to be coupled with PLC and PIP2 hydrolysis results in channel activation. Additional modes of TRPV1 sensitization comprise PKC‐ and PKA‐dependent pathways. Activation of either G‐protein‐coupled receptors or tyrosine kinase receptors causes TRPV1 sensitization. Of pathophysiological interest is the finding that endogenous and exogenous molecules may also cause TRPV1. Recently, we found that exposure to 0.3–3% ethanol causes a remarkable increase in Ca2+ mobilization in capsaicin‐sensitive cultured DRG neurons of newborn rat, an effect that was inhibited by the TRPV1 antagonist capsazepine. Wild‐type human embryonic kidney (HEK) cells did not respond to ethanol, but transfection with the human TRPV1 conferred to these cells the ability to respond to ethanol (Ca2+ mobilization) in a capsazepine‐sensitive manner. Electrophysiological studies showed that ethanol dramatically potentiated currents activated by anandamide and protons, and that ethanol reduced the threshold temperature for TRPV1 activation by about 8°C. Thus, in the presence of ethanol, the physiological temperature of 37°C is a sufficient stimulus to activate TRPV1 on sensory neurons and activate their afferent and efferent functions. Ethanol can trigger attacks of asthma and migraine and aggravates the symptoms of GERD. Exposure to ethanol caused a Ca2+‐dependent release of neuropeptides (SP/CGRP) from slices of rat esophagus and dura mater and guinea‐pig airways and increased plasma extravasation in the rat oesophagus and dura mater and caused bronchoconstriction in vitro and in vivo in guinea pigs. All these responses were inhibited selectively by capsazepine. Activation of sensory neurons and neurogenic inflammatory responses via TRPV1 stimulation may contribute to the mechanism of attacks of migraine and to the worsening of GERD and asthma symptoms precipitated by alcohol ingestion.

Introduction: Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder.Methods: The effect of TRPV1 activation on the release of two main proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, was explored in activated microglial cells. Furthermore, in a group of 132 MS patients, the association between the cerebrospinal fluid (CSF) levels of TNF and IL-6 and a single nucleotide polymorphisms (SNP) influencing TRPV1 protein expression and function (rs222747) was assessed.Results: In in vitro experiments, TRPV1 stimulation by capsaicin significantly reduced TNF and IL-6 release by activated microglial cells. Moreover, the anti-inflammatory effect of TRPV1 activation was confirmed by another TRPV1 agonist, the resiniferatoxin (RTX), whose effects were significantly inhibited by the TRPV1 antagonist, 5-iodoresiniferatoxin (5-IRTX). Vice versa, BV2 pre-treatment with 5-IRTX increased the inflammatory response induced by LPS. Moreover, in MS patients, a significant association emerged between TRPV1 SNP rs222747 and CSF TNF levels. In particular, the presence of a G allele, known to result in increased TRPV1 protein expression and function, was associated to lower CSF levels of TNF.Conclusions: Our results indicate that TRPV1 influences central inflammation in MS by regulating cytokine release by activated microglial cells. The modulation of the endovanilloid system may represent a useful approach to contrast neuroinflammation in MS.

Bladder cancer (BLCA) is the second most common urologic cancer in the United States and worldwide and mostly affects the aging population. Despite several ongoing clinical trials, treatment paradigms for BLCA have not changed significantly. Here, we investigated the expression of transient receptor potential vanilloid type 4 (TRPV4) in patients with BLCA and its role in calcium influx, cell proliferation, and migration using normal human urothelial cells and BLCA cells. Bioinformatic analysis of the University of Alabama at Birmingham Cancer Data Analysis Portal and cBioPortal databases revealed that TRPV4 expression is significantly higher in human BLCA tissues than in normal adjacent tissues. Furthermore, TRPV4 expression was markedly elevated in early-stage BLCA and upregulated in muscle-invasive bladder cancer tissues. TRPV4 is expressed in both normal urothelial (SV-HUC-1) and BLCA (T-24) cells, and functional assays demonstrated enhanced TRPV4-mediated calcium influx in T-24 compared with SV-HUC-1 cells. T-24 cells exhibited higher spreading on extracellular matrix gels with increasing stiffness (0.2, 8, and 50 kPa) and exhibited a migratory phenotype compared to SV-HUC-1 cells. Pharmacological inhibition of TRPV4 significantly reduced proliferation and migration in T-24 cells but had minimal effects on normal cells. Finally, treatment with cisplatin significantly reduced TRPV4 protein levels and TRPV4-mediated calcium influx in chemosensitive UM-UC-3 cells but remained unchanged in chemoresistant T-24 cells, suggesting a potential role of TRPV4 in chemoresistance. In conclusion, TRPV4 may contribute to BLCA progression by regulating cell proliferation and migration and may impart resistance to chemotherapy. Targeting TRPV4 could present a novel therapeutic approach for managing BLCA progression and overcoming chemoresistance.Significance StatementThis study identified transient receptor potential vanilloid type 4 (TRPV4) as a critical driver of bladder cancer (BLCA) progression. TRPV4 gene expression is elevated in both early-stage and muscle-invasive BLCA tissues. Importantly, TRPV4 inhibition selectively reduces BLCA growth and motility. Furthermore, TRPV4 is downregulated by cisplatin in chemosensitive but not chemoresistant BLCA cells, underscoring its key role in bladder cancer chemoresistance. These findings position TRPV4 as a therapeutic target for enhancing BLCA treatment and overcoming drug resistance.

Transient receptor potential vanilloid-type 4 (TRPV4) cation channel is widely expressed in all tissues as well as in immune cells and its function as mechanosensitive Ca2+ channel seems to be conserved throughout all mammalian species. Of late, emerging evidence has implicated TRPV4 in the activation and differentiation of innate immune cells, especially in neutrophils, monocytes, and macrophages. As such, TRPV4 has been shown to mediate neutrophil adhesion and chemotaxis, as well as production of reactive oxygen species in response to pro-inflammatory stimuli. In macrophages, TRPV4 mediates formation of both reactive oxygen and nitrogen species, and regulates phagocytosis, thus facilitating bacterial clearance and resolution of infection. Importantly, TRPV4 may present a missing link between mechanical forces and immune responses. This connection has been exemplary highlighted by the demonstrated role of TRPV4 in macrophage activation and subsequent induction of lung injury following mechanical overventilation. Mechanosensation via TRPV4 is also expected to activate innate immune cells and establish a pro-inflammatory loop in fibrotic diseases with increased deposition of extracellular matrix (ECM) and substrate stiffness. Likewise, TRPV4 may be activated by cell migration through the endothelium or the extracellular matrix, or even by circulating immune cells squeezing through the narrow passages of the pulmonary or systemic capillary bed, a process that has recently been linked to neutrophil priming and depriming. Here, we provide an overview over the emerging role of TRPV4 in innate immune responses and highlight two distinct modes for the activation of TRPV4 by either mechanical forces (“mechanoTRPV4”) or by pathogens (“immunoTRPV4”).

Cannabinoid receptor 1 suppresses transient receptor potential vanilloid 1-induced inflammatory responses to corneal injury

ABSTRACTObjective: Memory impairment induced by biliary cirrhosis is associated with abnormalities in the function of different neurotransmitter systems. However, the exact molecular mechanisms involved in the learning and memory dysfunctions following biliary cirrhosis is largely unknown. This study set out to determine whether activation of transient receptor potential vanilloid type 1 (TRPV1) in the CA1 area of the hippocampus in rats improve memory impairment induced by biliary cirrhosis.Methods: To assess learning and memory, passive avoidance task was carried out using a shuttle box. The mRNA expression of TRPV1 and cAMP response element binding (CREB) protein in the hippocampus were also evaluated by qT-PCR.Results: Our results indicated that activation of TRPV1 channels by capsaicin significantly decreased memory impairment and increased mRNA expression of the TRPV1 and CREB in the hippocampus of rats with biliary cirrhosis. Our findings also demonstrated that a positive correlation existed between mRNA expression of TRPV1 and CREB, and between memory function and TRPV1 expression.Discussion: Taken together, the results of this study support the view that TRPV1 receptor may play an important role in the regulation of learning and memory functions, and suggest that activation of TRPV1 channels seems to be a promising therapeutic target for learning and memory impairments following biliary cirrhosis.

BackgroundThe transient receptor potential vanilloid type1 (TRPV1) is expressed in nociceptive sensory neurons and is sensitive to phosphorylation. A-Kinase Anchoring Protein 79/150 (AKAP150) mediates phosphorylation of TRPV1 by Protein Kinases A and C, modulating channel activity. However, few studies have focused on the regulatory mechanisms that control AKAP150 association with TRPV1. In the present study, we identify a role for calcium/calmodulin in controlling AKAP150 association with, and sensitization of, TRPV1.ResultsIn trigeminal neurons, intracellular accumulation of calcium reduced AKAP150 association with TRPV1 in a manner sensitive to calmodulin antagonism. This was also observed in transfected Chinese hamster ovary (CHO) cells, providing a model for conducting molecular analysis of the association. In CHO cells, the deletion of the C-terminal calmodulin-binding site of TRPV1 resulted in greater association with AKAP150, and increased channel activity. Furthermore, the co-expression of wild-type calmodulin in CHOs significantly reduced TRPV1 association with AKAP150, as evidenced by total internal reflective fluorescence-fluorescence resonance energy transfer (TIRF-FRET) analysis and electrophysiology. Finally, dominant-negative calmodulin co-expression increased TRPV1 association with AKAP150 and increased basal and PKA-sensitized channel activity.Conclusionsthe results from these studies indicate that calcium/calmodulin interferes with the association of AKAP150 with TRPV1, potentially extending resensitization of the channel.

Signaling mechanisms of down-regulation of voltage-activated Ca2+ channels by transient receptor potential vanilloid type 1 stimulation with olvanil in primary sensory neurons

Initiated by the activation of various nociceptors, pain is a reaction to specific stimulus modalities. The μ-opioid receptor (MOR) agonists, including morphine, remain the most potent analgesics to treat patients with moderate to severe pain. However, the utility of MOR agonists is limited by the adverse effects associated with the use of these drugs, including analgesic tolerance and physical dependence. A strong connection has been suggested between the expression of the transient receptor potential vanilloid type 1 (TRPV1) ion channel and the development of inflammatory hyperalgesia. TRPV1 is important for thermal nociception induction, and is mainly expressed on sensory neurons. Recent reports suggest that opioid or TRPV1 receptor agonist exposure has contrasting consequences for anti-nociception, tolerance and dependence. Chronic morphine exposure modulates TRPV1 activation and induces the anti-nociception effects of morphine. The regulation of many downstream targets of TRPV1 plays a critical role in this process, including calcitonin gene-related peptide (CGRP) and substance P (SP). Additional factors also include capsaicin treatment blocking the anti-nociception effects of morphine in rats, as well as opioid modulation of TRPV1 responses through the cAMP-dependent PKA pathway and MAPK signaling pathways. Here, we review new insights concerning the mechanism underlying MOR-TRPV1 crosstalk and signaling pathways and discuss the potential mechanisms of morphine-induced anti-nociception, tolerance and dependence associated with the TRPV1 signaling pathway and highlight how understanding these mechanisms might help find therapeutic targets for the treatment of morphine induced antinociception, tolerance and dependence.

Transient receptor potential vanilloid type 1 (TRPV1), a nonselective cation channel, is a well-known pain-related receptor. TRPV1 involvement in morphine-induced antinociception, tolerance, and withdrawal symptoms has been previously reported. Emerging evidence indicates that TRPV1 may be related to both the cellular and behavioral effects of addictive drugs. In the present study, we investigated the role of TRPV1 in morphine reward using the conditioned place preference (CPP) paradigm in mice. Repeated morphine treatments upregulated TRPV1 expression in the dorsal striatum (DSt). Treatment with a TRPV1 agonist potentiated morphine reward, and pretreatment with TRPV1 antagonists attenuated these effects. Microinjection of a selective TRPV1 antagonist into the DSt significantly inhibited morphine-CPP. In addition, treatment with a TRPV1 antagonist suppressed morphine-induced increases in μ-opioid receptor binding, adenylyl cyclase 1 (AC1), p38 mitogen-activated protein kinase (p38 MAPK), and nuclear factor kappa B (NF-κB) expression in the DSt. Administering a p38 inhibitor not only prevented morphine-CPP, but also prevented morphine-induced NF-κB and TRPV1 activation in the DSt. Furthermore, injecting an NF-κB inhibitor significantly blocked morphine-CPP. Our findings suggest that TRPV1 in the DSt contribute to morphine reward via AC1, p38 MAPK, and NF-κB. Brain TRPV1 may serve as a novel therapeutic target to treat morphine-addictive disorders.

Prostaglandin E2 inhibits the proinflammatory phenotype induced by TGF-β on monocyte-derived dendritic cells

Prolonged exposure to bradykinin and prostaglandin E2 increases TRPV1 mRNA but does not alter TRPV1 and TRPV1b protein expression in cultured rat primary sensory neurons

Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel that is intensively expressed in the peripheral nerve system and involved in a variety of physiological and pathophysiological processes in mammals. Its activity is of great significance in transmitting pain or itch signals from peripheral sensory neurons to the central nervous system. The alteration or hypersensitivityof TRPV1 channelis well evidenced under variouspathological conditions. Moreover, accumulative studies have revealed that TRPV1-expressing (TRPV1+) sensory neurons mediate the neuroimmune crosstalk by releasing neuropeptides to innervated tissues as well as immune cells. In the central projection, TRPV1+ terminals synapse with the secondary neurons for the transmissionof pain and itch signalling. The intense involvement of TRPV1 and TRPV1+ neurons in pain and itch makes it a potential pharmaceutical target. Over decades, the basis of TRPV1 channel structure, the nature of its activity, and its modulation in pathological processes have been broadly studied and well documented. Herein, we highlight the role of TRPV1 and its associated neurons in sensing pain and itch. The fundamental understandings of TRPV1-involved nociception, pruriception, neurogenic inflammation, and cell-specific modulation will help bring out more effective strategies of TRPV1 modulation in treating pain- and itch-related diseases.

The cell-impermeant lidocaine derivative QX-314 blocks sodium channels via intracellular mechanisms. In somatosensory nociceptive neurons, open transient receptor potential vanilloid type 1 (TRPV1) receptors provide a transmembrane passageway for QX-314 to produce long-lasting analgesia. Many cranial primary afferents express TRPV1 at synapses on neurons in the nucleus of the solitary tract and caudal trigeminal nucleus (Vc). Here, we investigated whether QX-314 interrupts neurotransmission from primary afferents in rat brain-stem slices. Shocks to the solitary tract (ST) activated highly synchronous evoked excitatory postsynaptic currents (ST-EPSCs). Application of 300 μM QX-314 increased the ST-EPSC latency from TRPV1+ ST afferents, but, surprisingly, it had similar actions at TRPV1- ST afferents. Continued exposure to QX-314 blocked evoked ST-EPSCs at both afferent types. Neither the time to onset of latency changes nor the time to ST-EPSC failure differed between responses for TRPV1+ and TRPV1- inputs. Likewise, the TRPV1 antagonist capsazepine failed to prevent the actions of QX-314. Whereas QX-314 blocked ST-evoked release, the frequency and amplitude of spontaneous EPSCs remained unaltered. In neurons exposed to QX-314, intracellular current injection evoked action potentials suggesting a presynaptic site of action. QX-314 acted similarly at Vc neurons to increase latency and block EPSCs evoked from trigeminal tract afferents. Our results demonstrate that QX-314 blocked nerve conduction in cranial primary afferents without interrupting the glutamate release mechanism or generation of postsynaptic action potentials. The TRPV1 independence suggests that QX-314 either acted extracellularly or more likely entered these axons through an undetermined pathway common to all cranial primary afferents.

Transient receptor potential vanilloid type 4 (TRPV4) is a versatile ion channel with diverse roles in immune cells, including macrophages. While its function in inflammation remains debated, we investigated its role in regulating IL-10 production and its impact on macrophage reprogramming during inflammation. We investigated the connection between TRPV4 activation and CREB-mediated IL-10 production during inflammation. Notably, this signaling pathway was found to reprogram macrophages and enhance their ability to resist inflammatory damage. The experiments were conducted on primary macrophages and were further corroborated by animal studies. In response to TRPV4 activation during inflammation, we observed a significant increase in intracellular Ca2+ levels, which triggered the activation of the transcription factor CREB, subsequently upregulating IL-10 production. This IL-10 played a pivotal role in reprogramming macrophages to withstand inflammatory damage. Using a mouse model of acute lung injury (ALI), we confirmed that TRPV4 activation during ALI led to IL-10 secretion, but this increase did not significantly contribute to inflammation resolution. Moreover, we found that TRPV4 prevented the accumulation of dysfunctional mitochondria in macrophages through the CREB-IL-10 axis during inflammation. Suppression of CREB or TRPV4 inhibition exacerbated mitochondrial dysfunction, while treatment with recombinant IL-10 mitigated these effects. Additionally, IL-10 induced mitophagy and cleared dysfunctional mitochondria in LPS-exposed cells. Our study highlights the essential role of TRPV4 in regulating IL-10 production and mitochondrial health in macrophages during inflammation. These findings contribute to understand the role of TRPV4 in immune responses and suggest potential therapeutic targets for modulating inflammation-induced cellular dysfunction.