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1
Sharma, Deep, Rekha Rana, and Kiran Thakur. "A REVIEW ON ROLE OF TRPV CATION CHANNELS." Journal of Biomedical and Pharmaceutical Research 10, no. 2 (March 30, 2021): 32–51. http://dx.doi.org/10.32553/jbpr.v10i2.857.
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The mammalian branch of the Transient Receptor Potential (TRP) superfamily of cation channels consists of 28 members. They can be subdivided in six main subfamilies: the TRPC (‘Canonical’), TRPV (‘Vanilloid’), TRPM (‘Melastatin’), TRPP (‘Polycystin’), TRPML (‘Mucolipin’) and the TRPA (‘Ankyrin’) group. The TRPV subfamily comprises channels that are critically involved in nociception and thermo-sensing (TRPV1, TRPV2, TRPV3, TRPV4) as well as highly Ca2+ selective channels involved in Ca2+ absorption/ reabsorption in mammals (TRPV5, TRPV6). In this review we summarize fundamental physiological properties of all TRPV members in the light of various cellular functions of these channels and their significance in the various diseases.
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Chung, Gehoon, and Seog Bae Oh. "TRP Channels in Dental Pain." Open Pain Journal 6, no. 1 (March 8, 2013): 31–36. http://dx.doi.org/10.2174/1876386301306010031.
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Despite the high incidence of dental pain, the mechanism underlying its generation is mostly unknown. Functional expression of temperature-sensitive transient receptor potential (thermo-TRP) channels, such as TRPV1, TRPV2, TRPM8, and TRPA1 in dental primary afferent neurons and TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3 in odontoblasts, has been demonstrated and suggested as responsible for dental pain elicited by hot and cold food. However, dental pain induced by light touch or sweet substance cannot be explained by the role of thermo-TRP channels. Most of current therapeutics of dentin hypersensitivity is based on hydrodynamic theory, which argues that light stimuli such as air puff and temperature changes cause fluid movement within dentinal tubule, which is then transduced as pain. To test this theory, various TRP channels as candidates of cellular mechanotransducers were studied for expression in dental primary afferents and odontoblasts. The expression of TRPV1, TRPV2, TRPA1, TRPV4, and TRPM3 in trigeminal neurons and TRPV1, TRPV2, TRPV3, TRPV4 and TRPM3 in odontoblasts has been revealed. However, their roles as cellular mechanotransducers are controversial and contribution to generation of dental pain is still elusive. This review discusses recent advances in understanding of molecular mechanism underlying development of dental pain.
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Marshall-Gradisnik, Sonya M., Peter Smith, Ekua W. Brenu, Bernd Nilius, Sandra B. Ramos, and Donald R. Staines. "Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients." Immunology and Immunogenetics Insights 7 (January 2015): III.S25147. http://dx.doi.org/10.4137/iii.s25147.
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Background The transient receptor potential (TRP) superfamily in humans comprises 27 cation channels with permeability to monovalent and divalent cations. These channels are widely expressed within humans on cells and tissues and have significant sensory and regulatory roles on most physiological functions. Chronic fatigue syndrome (CFS) is an unexplained disorder with multiple physiological impairments. OBJECTIVES The purpose of this study was to determine the role of TRPs in CFS. Methods The study comprised 115 CFS patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years). CFS patients were defined according to the 1994 Center for Disease Prevention and Control criteria for CFS. A total of 240 single nucleotide polymorphisms (SNPs) for 21 mammalian TRP ion channel genes ( TRPA1, TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software. Results Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P < 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P < 0.013, rs1328153; P < 0.013, rs3763619; P < 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P ≤ 0.016, rs655207; P ≤ 0.018). Conclusion The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS.
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Toledo Mauriño, Joel J., Gabriela Fonseca-Camarillo, Janette Furuzawa-Carballeda, Rafael Barreto-Zuñiga, Braulio Martínez Benítez, Julio Granados, and Jesus K. Yamamoto-Furusho. "TRPV Subfamily (TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) Gene and Protein Expression in Patients with Ulcerative Colitis." Journal of Immunology Research 2020 (May 8, 2020): 1–11. http://dx.doi.org/10.1155/2020/2906845.
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Introduction. TRPVs are a group of receptors with a channel activity predominantly permeable to Ca2+. This subfamily is involved in the development of gastrointestinal diseases such as ulcerative colitis (UC). The aim of the study was to characterize the gene and protein expression of the TRPV subfamily in UC patients and controls. Methods. We determined by quantitative PCR the gene expression of TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6 in 45 UC patients (29 active UC and 16 remission UC) and 26 noninflamed controls. Protein expression was evaluated in 5 μm thick sections of formalin-fixed, paraffin-embedded tissue from 5 customized severe active UC patients and 5 control surgical specimens. Results. TRPV2 gene expression was increased in the control group compared with active UC and remission patients (P=0.002 and P=0.05, respectively). TRPV3 gene expression was significantly higher in controls than in active UC patients (P=0.002). The gene expression of TRPV4 was significantly higher in colonic tissue from patients with remission UC compared with active UC patients (P=0.05) and controls (P=0.005). TRPV5 had significantly higher mRNA levels in a control group compared with active UC patients (P=0.02). The gene expression of TRPV6 was significantly higher in the colonic tissue from patients with active UC compared with the control group (P=0.05). The protein expression of TRPV2 was upregulated in the mucosa and submucosa from the controls compared with the UC patients (P≤0.003). The protein expression of TRPV3 and TRPV4 was upregulated in all intestinal layers from the controls compared with the UC patients (P<0.001). TRPV5 was upregulated in the submucosa and serosa from the controls vs. UC patients (P<0.001). TRPV6 was upregulated in all intestinal layers from the UC patients vs. controls (P≤0.001). Conclusion. The TRPV subfamily clearly showed a differential expression in the UC patients compared with the controls, suggesting their role in the pathophysiology of UC.
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Kotova, O. O. "Modern concepts of the role of transient receptor potential channel vanilloid subfamily (TRPV) in development osmotic airway hyperresponsiveness in asthma patients (review)." Bulletin Physiology and Pathology of Respiration, no. 81 (September 29, 2021): 115–25. http://dx.doi.org/10.36604/1998-5029-2021-81-115-125.
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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.
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Yang, Xiao-Ru, Mo-Jun Lin, Lionel S. McIntosh, and James S. K. Sham. "Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 6 (June 2006): L1267—L1276. http://dx.doi.org/10.1152/ajplung.00515.2005.
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Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel subtypes have been identified and cloned in different tissues. However, their information in vascular tissue is scant. In this study, we sought to identify TRPM and TRPV channel subtypes expressed in rat deendothelialized intralobar pulmonary arteries (PAs) and aorta. With RT-PCR, mRNA of TRPM2, TRPM3, TRPM4, TRPM7, and TRPM8 of TRPM family and TRPV1, TRPV2, TRPV3, and TRPV4 of TRPV family were detected in both PAs and aorta. Quantitative real-time RT-PCR showed that TRPM8 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Moreover, Western blot analysis verified expression of TRPM2, TRPM8, TRPV1, and TRPV4 proteins in both types of vascular tissue. To examine the functional activities of these channels, we monitored intracellular Ca2+ transients ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) and aortic smooth muscle cells (ASMCs). The TRPM8 agonist menthol (300 μM) and the TRPV4 agonist 4α-phorbol 12,13-didecanoate (1 μM) evoked significant increases in [Ca2+]i in PASMCs and ASMCs. These Ca2+ responses were abolished in the absence of extracellular Ca2+ or the presence of 300 μM Ni2+ but were unaffected by 1 μM nifedipine, suggesting Ca2+ influx via nonselective cation channels. Hence, for the first time, our results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta. These novel Ca2+ entry pathways may play important roles in the regulation of pulmonary and systemic circulation.
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Zhang, Lei, Sarahlouise Jones, Kate Brody, Marcello Costa, and Simon J. H. Brookes. "Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse." American Journal of Physiology-Gastrointestinal and Liver Physiology 286, no. 6 (June 2004): G983—G991. http://dx.doi.org/10.1152/ajpgi.00441.2003.
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A number of transient receptor potential (TRP) channels has recently been shown to mediate cutaneous thermosensitivity. Sensitivity to warm and cool stimuli has been demonstrated in both human and animal gastrointestinal tract; however, the molecular mechanisms that underlie this have not been determined. Vagal afferent neurons with cell bodies in the nodose ganglion are known to mediate nonnociceptive sensation from the upper gut. In this study, isolated cultured nodose ganglion from the mouse neurons showed changes in cytoplasmic-free Ca2+concentrations over a range of temperatures, as well as to icilin (a TRPM8 and TRPN1 agonist) and capsaicin (a TRPV1 agonist). RT-PCR was used to show the presence of six temperature-sensitive TRP channel transcripts (TRPV1–4, TRPN1, and TRPM8) in whole nodose ganglia. In addition, RT-PCR of single nodose cell bodies, which had been retrogradely labeled from the upper gut, detected transcripts for TRPV1, TRPV2, TRPV4, TRPN1, and TRPM8 in a proportion of cells. Immunohistochemical labeling detected TRPV1 and TRPV2 proteins in nodose ganglia. The presence of TRP channel transcripts and proteins was also detected in cells within several regions of the gastrointestinal tract. Our results reveal that TRP channels are present in subsets of vagal afferent neurons that project to the stomach and may confer temperature sensitivity on these cells.
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Peng, Gongyong, Wenju Lu, Xiaoyan Li, Yuqin Chen, Nanshan Zhong, Pixin Ran, and Jian Wang. "Expression of store-operated Ca2+ entry and transient receptor potential canonical and vanilloid-related proteins in rat distal pulmonary venous smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 299, no. 5 (November 2010): L621—L630. http://dx.doi.org/10.1152/ajplung.00176.2009.
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Chronic hypoxia causes remodeling and alters contractile responses in both pulmonary arteries and pulmonary veins. Although pulmonary arteries have been studied extensively in these disorders, the mechanisms by which pulmonary veins respond to hypoxia and whether these responses contribute to chronic hypoxic pulmonary hypertension remain poorly understood. In pulmonary arterial smooth muscle, we have previously demonstrated that influx of Ca2+ through store-operated calcium channels (SOCC) thought to be composed of transient receptor potential (TRP) proteins is likely to play an important role in development of chronic hypoxic pulmonary hypertension. To determine whether this mechanism could also be operative in pulmonary venous smooth muscle, we measured intracellular Ca2+ concentration ([Ca2+]i) by fura-2 fluorescence microscopy in primary cultures of pulmonary venous smooth muscle cells (PVSMC) isolated from rat distal pulmonary veins. In cells perfused with Ca2+-free media containing cyclopiazonic acid (10 μM) and nifedipine (5 μM) to deplete sarcoplasmic reticulum Ca2+ stores and block voltage-dependent Ca2+ channels, restoration of extracellular Ca2+ (2.5 mM) caused marked increases in [Ca2+]i, whereas MnCl2 (200 μM) quenched fura-2 fluorescence, indicating store-operated Ca2+ entry (SOCE). SKF-96365 and NiCl2, antagonists of SOCC, blocked SOCE at concentrations that did not alter Ca2+ responses to 60 mM KCl. Of the seven known canonical TRP (TRPC1–7) and six vanilloid-related TRP channels (TRPV1–6), real-time PCR revealed mRNA expression of TRPC1 > TRPC6 > TRPC4 > TRPC2 ≈ TRPC5 > TRPC3, TRPV2 > TRPV4 > TRPV1 in distal PVSMC, and TRPC1 > TRPC6 > TRPC3 > TRPC4 ≈ TRPC5, TRPV2 ≈ TRPV4 > TRPV1 in rat distal pulmonary vein (PV) smooth muscle. Western blotting confirmed protein expression of TRPC1, TRPC6, TRPV2, and TRPV4 in both PVSMC and PV. Our results suggest that SOCE through Ca2+ channels composed of TRP proteins may contribute to Ca2+ signaling in rat distal PV smooth muscle.
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Kuwashima, Yutaro, Masataka Yanagawa, Mitsuhiro Abe, Michio Hiroshima, Masahiro Ueda, Makoto Arita, and Yasushi Sako. "Comparative Analysis of Single-Molecule Dynamics of TRPV1 and TRPV4 Channels in Living Cells." International Journal of Molecular Sciences 22, no. 16 (August 6, 2021): 8473. http://dx.doi.org/10.3390/ijms22168473.
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TRPV1 and TRPV4, members of the transient receptor potential vanilloid family, are multimodal ion channels activated by various stimuli, including temperature and chemicals. It has been demonstrated that TRPV channels function as tetramers; however, the dynamics of the diffusion, oligomerization, and endocytosis of these channels in living cells are unclear. Here we undertook single-molecule time-lapse imaging of TRPV1 and TRPV4 in HEK 293 cells. Differences were observed between TRPV1 and TRPV4 before and after agonist stimulation. In the resting state, TRPV4 was more likely to form higher-order oligomers within immobile membrane domains than TRPV1. TRPV1 became immobile after capsaicin stimulation, followed by its gradual endocytosis. In contrast, TRPV4 was rapidly internalized upon stimulation with GSK1016790A. The selective loss of immobile higher-order oligomers from the cell surface through endocytosis increased the proportion of the fast-diffusing state for both subtypes. With the increase in the fast state, the association rate constants of TRPV1 and TRPV4 increased, regenerating the higher-order oligomers. Our results provide a possible mechanism for the different rates of endocytosis of TRPV1 and TRPV4 based on the spatial organization of the higher-order structures of the two TRPV channels.
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Yoo, Hae Young, Su Jung Park, Eun-Young Seo, Kyung Sun Park, Jung-A. Han, Kyung Soo Kim, Dong Hoon Shin, Yung E. Earm, Yin-Hua Zhang, and Sung Joon Kim. "Role of thromboxane A2-activated nonselective cation channels in hypoxic pulmonary vasoconstriction of rat." American Journal of Physiology-Cell Physiology 302, no. 1 (January 2012): C307—C317. http://dx.doi.org/10.1152/ajpcell.00153.2011.
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Hypoxia-induced pulmonary vasoconstriction (HPV) is critical for matching of ventilation/perfusion in lungs. Although hypoxic inhibition of K+ channels has been a leading hypothesis for depolarization of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia, pharmacological inhibition of K+ channels does not induce significant contraction in rat pulmonary arteries. Because a partial contraction by thromboxane A2 (TXA2) is required for induction of HPV, we hypothesize that TXA2 receptor (TP) stimulation might activate depolarizing nonselective cation channels (NSCs). Consistently, we found that 5–10 nM U46619, a stable agonist for TP, was indispensible for contraction of rat pulmonary arteries by 4-aminopyridine, a blocker of voltage-gated K+ channel (Kv). Whole cell voltage clamp with rat PASMC revealed that U46619 induced a NSC current ( INSC,TXA2) with weakly outward rectifying current-voltage relation. INSC,TXA2 was blocked by ruthenium red (RR), an antagonist of the transient receptor potential vanilloid-related channel (TRPV) subfamily. 2-Aminoethoxydiphenyl borate, an agonist for TRPV1–3, consistently activated NSC channels in PASMCs. In contrast, agonists for TRPV1 (capsaicin), TRPV3 (camphor), or TRPV4 (α-PDD) rarely induced an increase in the membrane conductance of PASMCs. RT-PCR analysis showed the expression of transcripts for TRPV2 and -4 in rat PASMCs. Finally, it was confirmed that pretreatment with RR largely inhibited HPV in the presence of U46619. The pretreatment with agonists for TRPV1 (capsaicin) and TRPV4 (α-PDD) was ineffective as pretone agents for HPV. Taken together, it is suggested that the concerted effects of INSC,TXA2 activation and Kv inhibition under hypoxia induce membrane depolarization sufficient for HPV. TRPV2 is carefully suggested as the TXA2-activated NSC in rat PASMC.
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Blackshaw, L. Ashley, Stuart M. Brierley, Andrea M. Harrington, and Patrick A. Hughes. "TRP Channels in Visceral Pain." Open Pain Journal 6, no. 1 (March 8, 2013): 23–30. http://dx.doi.org/10.2174/1876386301306010023.
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Visceral pain is both different and similar to somatic pain - different in being poorly localized and usually referred elsewhere to the body wall, but similar in many of the molecular mechanisms it employs (like TRP channels) and the specialization of afferent endings to detect painful stimuli. TRPV1 is sensitive to low pH. pH is lowest in gastric juice, which may cause severe pain when exposed to the oesophageal mucosa, and probably works via TRPV1. TRPV1 is found in afferent fibres throughout the viscera, and the TRPV1 agonist capsaicin can recapitulate symptoms experienced in disease. TRPV1 is also involved in normal mechanosensory function in the gut. Roles for TRPV4 and TRPA1 have also been described in visceral afferents, and TRPV4 is highly enriched in them, where it plays a major role in both mechanonociception and chemonociception. It may provide a visceral-specific nociceptor target for drug development. TRPA1 is also involved in mechano-and chemosensory function, but not as selectively as TRPV4. TRPA1 is colocalized with TRPV1 in visceral afferents, where they influence each other's function. Another modulator of TRPV1 is the cool/mint receptor TRPM8, which, when activated can abrogate responses mediated via TRPV1, suggesting that TRPM8 agonists may provide analgesia via this pathway. In all, the viscera are rich in TRP channel targets on nociceptive neurones which we hope will provide opportunities for therapeutic analgesia.
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Nakazawa, Yosuke, Rosica S. Petrova, Yuki Sugiyama, Noriaki Nagai, Hiroomi Tamura, and Paul J. Donaldson. "Regulation of the Membrane Trafficking of the Mechanosensitive Ion Channels TRPV1 and TRPV4 by Zonular Tension, Osmotic Stress and Activators in the Mouse Lens." International Journal of Molecular Sciences 22, no. 23 (November 23, 2021): 12658. http://dx.doi.org/10.3390/ijms222312658.
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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.
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Gorbunov, Alexandr S., Leonid N. Maslov, Amteshwar S. Jaggi, Nirmal Singh, Luciano De Petrocellis, Alla A. Boshchenko, Ali Roohbakhsh, Vladimir V. Bezuglov, and Peter R. Oeltgen. "Physiological and Pathological Role of TRPV1, TRPV2 and TRPV4 Channels in Heart." Current Cardiology Reviews 15, no. 4 (August 19, 2019): 244–51. http://dx.doi.org/10.2174/1573403x15666190307112326.
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Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The knockout of the TRPV1 gene promotes increased tolerance of the isolated perfused heart to the impact of ischemia/reperfusion (I/R). However, activation of TRPV1 increases the resistance of the heart to I/R due to calcitonin gene-related peptide (CGRP) release from afferent nerve endings. It has been established that TRPV1 and TRPV2 are involved in the pathogenesis of myocardial infarction and, in all likelihood, ensure the cardiac tolerance to the ischemia/reperfusion. It has also been documented that the activation of TRPV4 negatively affects the stability of cardiomyocytes to the H/R. The blockade of TRPV4 can be considered as a new approach to the prevention of I/R injury of the heart. Studies also indicate that TRPV1 is involved in the pathogenesis of cardiac hypertrophy and that TRPV2 channels participate in the pathogenesis of dilated cardiomyopathy. Excessive expression of TRPV2 leads to chronic Ca2+- overload of cardiomyocytes, which may contribute to the development of cardiomyopathy.
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Lötsch, Jörn, Dario Kringel, Gerd Geisslinger, Bruno G. Oertel, Eduard Resch, and Sebastian Malkusch. "Machine-Learned Association of Next-Generation Sequencing-Derived Variants in Thermosensitive Ion Channels Genes with Human Thermal Pain Sensitivity Phenotypes." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4367. http://dx.doi.org/10.3390/ijms21124367.
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Genetic association studies have shown their usefulness in assessing the role of ion channels in human thermal pain perception. We used machine learning to construct a complex phenotype from pain thresholds to thermal stimuli and associate it with the genetic information derived from the next-generation sequencing (NGS) of 15 ion channel genes which are involved in thermal perception, including ASIC1, ASIC2, ASIC3, ASIC4, TRPA1, TRPC1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4. Phenotypic information was complete in 82 subjects and NGS genotypes were available in 67 subjects. A network of artificial neurons, implemented as emergent self-organizing maps, discovered two clusters characterized by high or low pain thresholds for heat and cold pain. A total of 1071 variants were discovered in the 15 ion channel genes. After feature selection, 80 genetic variants were retained for an association analysis based on machine learning. The measured performance of machine learning-mediated phenotype assignment based on this genetic information resulted in an area under the receiver operating characteristic curve of 77.2%, justifying a phenotype classification based on the genetic information. A further item categorization finally resulted in 38 genetic variants that contributed most to the phenotype assignment. Most of them (10) belonged to the TRPV3 gene, followed by TRPM3 (6). Therefore, the analysis successfully identified the particular importance of TRPV3 and TRPM3 for an average pain phenotype defined by the sensitivity to moderate thermal stimuli.
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Cheng, Li, Qing-Qing Luo, and Sheng-Liang Chen. "Expression of TRP Channels in Colonic Mucosa of IBS-D Patients and Its Correlation with the Severity of the Disease." Gastroenterology Research and Practice 2022 (May 29, 2022): 1–7. http://dx.doi.org/10.1155/2022/7294775.
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Aim. Lots of researches have endeavored to elucidate the pathogenetic mechanism of visceral hypersensitivity in order to guide the therapy of diarrhea predominant-irritable bowel syndrome (IBS-D). Transient receptor potential (TRP) channels and their role in visceral nociception have been vastly investigated. We investigated the expression of TRP channels in IBS-D colonic biopsies and its correlation with the severity of the disease. Methods. Sigmoid biopsies were obtained from 34 IBS-D patients and 28 healthy controls (HCs). IBS-D was diagnosed according to Rome IV criteria. Their clinical parameters were assessed through questionnaires. Expression of TRPV1, TRPV4, TRPA1, TRPM2, and TRPM8 was evaluated with immunohistology staining. Results. Expression levels of TRPV1, TRPV4, and TRPA1 in the colonic mucosa of IBS-D patients were significantly higher than those in HCs ( p < 0.05 ), while there was no obvious difference of TRPM2 and TRPM8 expression between IBS-D patients and HCs. In addition, the expression levels of TRPV1 and TRPA1, but TRPV4, in the colonic mucosa correlated positively with the severity of diseases ( r = 0.6303 and 0.4506, respectively, p < 0.05 ). Conclusions. Expression of TRPV1, TRPA1, and TRPV4 in the colonic mucosa was enhanced in IBS-D patients compared with HCs with the former two correlated with the severity of the disease. TRP channels might be promising biomarkers in the diagnosis and estimate of the severity in IBS-D.
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Kameda, Takuya, Joel Zvick, Miriam Vuk, Aleksandra Sadowska, Wai Kit Tam, Victor Y. Leung, Kata Bölcskei, et al. "Expression and Activity of TRPA1 and TRPV1 in the Intervertebral Disc: Association with Inflammation and Matrix Remodeling." International Journal of Molecular Sciences 20, no. 7 (April 10, 2019): 1767. http://dx.doi.org/10.3390/ijms20071767.
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Transient receptor potential (TRP) channels have emerged as potential sensors and transducers of inflammatory pain. The aims of this study were to investigate (1) the expression of TRP channels in intervertebral disc (IVD) cells in normal and inflammatory conditions and (2) the function of Transient receptor potential ankyrin 1 (TRPA1) and Transient receptor potential vanilloid 1 (TRPV1) in IVD inflammation and matrix homeostasis. RT-qPCR was used to analyze human fetal, healthy, and degenerated IVD tissues for the gene expression of TRPA1 and TRPV1. The primary IVD cell cultures were stimulated with either interleukin-1 beta (IL-1β) or tumor necrosis factor alpha (TNF-α) alone or in combination with TRPA1/V1 agonist allyl isothiocyanate (AITC, 3 and 10 µM), followed by analysis of calcium flux and the expression of inflammation mediators (RT-qPCR/ELISA) and matrix constituents (RT-qPCR). The matrix structure and composition in caudal motion segments from TRPA1 and TRPV1 wild-type (WT) and knock-out (KO) mice was visualized by FAST staining. Gene expression of other TRP channels (A1, C1, C3, C6, V1, V2, V4, V6, M2, M7, M8) was also tested in cytokine-treated cells. TRPA1 was expressed in fetal IVD cells, 20% of degenerated IVDs, but not in healthy mature IVDs. TRPA1 expression was not detectable in untreated cells and it increased upon cytokine treatment, while TRPV1 was expressed and concomitantly reduced. In inflamed IVD cells, 10 µM AITC activated calcium flux, induced gene expression of IL-8, and reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and collagen 1A1, possibly via upregulated TRPA1. TRPA1 KO in mice was associated with signs of degeneration in the nucleus pulposus and the vertebral growth plate, whereas TRPV1 KO did not show profound changes. Cytokine treatment also affected the gene expression of TRPV2 (increase), TRPV4 (increase), and TRPC6 (decrease). TRPA1 might be expressed in developing IVD, downregulated during its maturation, and upregulated again in degenerative disc disease, participating in matrix homeostasis. However, follow-up studies with larger sample sizes are needed to fully elucidate the role of TRPA1 and other TRP channels in degenerative disc disease.
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Huang, Susan M., and Man-Kyo Chung. "Targeting TRPV3 for the Development of Novel Analgesics." Open Pain Journal 6, no. 1 (March 8, 2013): 119–26. http://dx.doi.org/10.2174/1876386301306010119.
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Decades of characterization of the transient receptor potential vanilloid subtype 1 (TRPV1) have led to the realization of its central role in thermosensation and pain perception. A large number of pharmaceutical companies have had interest in developing TPRV1 antagonists for the treatment of pain. The subsequent discovery of multiple other members of this TRPV family has not gone unnoticed. TRPV3 exhibits approximately 40% homology to TRPV1, and has common as well as distinct features from TRPV1 in channel physiology, expression and function. Here we review the current understanding of TRPV3 channel biology, activation, sensitization and the consequences of TRPV3 manipulation for thermosensation and nociception, as well as additional considerations regarding the expression of TRPV3 in the skin. We weigh in on the available evidence in the context of potential development of TRPV3 modulating agents as analgesics.
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Liedtke, Wolfgang. "Transient receptor potential vanilloid channels functioning in transduction of osmotic stimuli." Journal of Endocrinology 191, no. 3 (December 2006): 515–23. http://dx.doi.org/10.1677/joe.1.07000.
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In signal transduction of metazoan cells, ion channels of the family of transient receptor potential (TRP) have been identified to respond to diverse external and internal stimuli, amongst them osmotic stimuli. This review will highlight findings on the TRPV subfamily, both vertebrate and invertebrate members. Out of the six mammalian TRP vanilloid (TRPV) channels, TRPV1, TRPV2, and TRPV4 were demonstrated to function in transduction of osmotic stimuli. TRPV channels have been found to function in cellular as well as systemic osmotic homeostasis in vertebrates. Invertebrate TRPV channels, five in Caenorhabditis elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to osmotic stimuli in C. elegans. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue osmo-and mechanosensory deficits of the TRPV mutant strain osm-9 in C. elegans, despite not more than 26% orthology of the respective proteins.
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Ghoneum, Mamdooh, James Gimzewski, Aya Ghoneum, Hideki Katano, Clarissa Paw U, and Anshu Agrawal. "Inhibition of TRPV1 Channel Activity in Human CD4+ T Cells by Nanodiamond and Nanoplatinum Liquid, DPV576." Nanomaterials 8, no. 10 (September 29, 2018): 770. http://dx.doi.org/10.3390/nano8100770.
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Background: Transient receptor potential vanilloid (TRPV) channels act as sensors of pain, temperature, and other external stimuli. We have recently shown that DPV576, an aqueous mixture of nanodiamond (ND) and nanoplatinum (NP), can modulate the activity of TRPV on human primary keratinocytes, suggesting their potential as a possible pain modulator. Here, we sought to examine the effect of DPV576 in modulating the functions of human CD4+ T lymphocytes and whether the modulation is mediated via TRPV channels. Materials and methods: Human primary CD4+ T cells were activated with anti CD3/CD28 with and without DPV576 at 1:10 and 1:100 dilutions for 24 h in vitro. TRPV receptor expression (TRPV1 and TRPV4) on CD4+ T cells were examined by flow cytometry. The capacity of DPV576 to modulate the activity of TRPV1 agonist capsaicin in CD4+ T cells was also determined. Activation of CD4+ T cells was determined by production of cytokines TNF-α, IFN-γ, and IL-10 using specific ELISA kits. Results: DPV576 treatment of CD4+ T cells that were activated with anti CD3/CD28 resulted in decreased expression of the TRPV1 channel, but had no effect on TRPV4. This was accompanied by decreased secretion of IFN-γ and reduced expression of TRPV1 in capsaicin activated CD4+ T cells. In addition, DPV576 inhibited the capsaicin, induced the production of IFN-γ, and enhanced the secretion of IL-10. Conclusion: We conclude that short term exposure to DPV576 inhibits the activity of TRPV1 channels in CD4+ T lymphocytes, which may suggest its possible beneficial use for pain management.
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Naumov, D. E., I. Yu Sugaylo, O. O. Kotova, D. A. Gassan, Ya G. Gorchakova, and T. A. Maltseva. "Comparative characteristics of TRP channels expression levels on the macrophages of patients with chronic obstructive pulmonary disease." Bulletin Physiology and Pathology of Respiration, no. 85 (September 22, 2022): 37–46. http://dx.doi.org/10.36604/1998-5029-2022-85-37-46.
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Introduction. Macrophages are one of the key cells in the pathogenesis of chronic obstructive pulmonary disease (COPD), mediating the primary immune response and coordinating the further reaction of the immune system upon contact with cigarette smoke and air pollutants. It is known that some TRP channels expressed on macrophages are receptors for dust particles and cigarette smoke components.Aim. To study the features of TRPV1, TRPV4, TRPA1 and TRPM8 channels expression on monocyte-derived macrophages and alveolar macrophages of COPD patients and smokers without bronchial obstruction.Materials and methods. Expression of TRP channels at the mRNA level was studied in monocyte-derived macrophages obtained from 8 COPD patients and 6 healthy smokers by quantitative reverse transcription PCR. Expression of TRP channels at the protein level was studied on alveolar macrophages of 39 COPD patients and 8 healthy smokers by indirect flow cytometry.Results. It was found that under in vitro conditions, monocyte-derive macrophages of COPD patients were distinguished by a significant 4.8-fold increase in the number of TRPV1 transcripts (p=0.009). At the same time, the expression of the TRPV1 protein on the alveolar macrophages of COPD patients was also significantly higher when compared to the cells of smokers from the control group (14.1 [6.4‒21.2]% vs. 6.1 [2.1‒9.8]%, p=0.006). In addition, we found that TRPV4 expression was increased among active smokers with COPD, and the expression of TRPA1 and TRPM8 channels correlated with some lung function parameters.Conclusion. The obtained results suggest that the increased expression of TRPV1 on macrophages may be a marker of the disease and contribute to its development, while the expression of TRPV4, TRPA1 and TRPM8 may influence the clinical course of COPD.
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Zhang, Hongyu, Peter J. Wickley, Sayantani Sinha, Ian N. Bratz, and Derek S. Damron. "Propofol Restores Transient Receptor Potential Vanilloid Receptor Subtype-1 Sensitivity via Activation of Transient Receptor Potential Ankyrin Receptor Subtype-1 in Sensory Neurons." Anesthesiology 114, no. 5 (May 1, 2011): 1169–79. http://dx.doi.org/10.1097/aln.0b013e31820dee67.
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Background Cross talk between peripheral nociceptors belonging to the transient receptor potential vanilloid receptor subtype-1 (TRPV1) and ankyrin subtype-1 (TRPA1) family has been demonstrated recently. Moreover, the intravenous anesthetic propofol has directly activates TRPA1 receptors and indirectly restores sensitivity of TRPV1 receptors in dorsal root ganglion (DRG) sensory neurons. Our objective was to determine the extent to which TRPA1 activation is involved in mediating the propofol-induced restoration of TRPV1 sensitivity. Methods Mouse DRG neurons were isolated by enzymatic dissociation and grown for 24 h. F-11 cells were transfected with complementary DNA for both TRPV1 and TRPA1 or TRPV1 only. The intracellular Ca concentration was measured in individual cells via fluorescence microscopy. After TRPV1 desensitization with capsaicin (100 nM), cells were treated with propofol (1, 5, and 10 μM) alone or with propofol in the presence of the TRPA1 antagonist, HC-030031 (0.5 μM), or the TRPA1 agonist, allyl isothiocyanate (AITC; 100 μM); capsaicin was then reapplied. Results In DRG neurons that contain both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in DRG neurons containing only TRPV1 receptors, exposure to propofol or AITC after desensitization did not restore capsaicin-induced TRPV1 sensitivity. Similarly, in F-11 cells transfected with both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in F-11 cells transfected with TRPV1 only, neither propofol nor AITC was capable of restoring TRPV1 sensitivity. Conclusions These data demonstrate that propofol restores TRPV1 sensitivity in primary DRG neurons and in cultured F-11 cells transfected with both the TRPV1 and TRPA1 receptors via a TRPA1-dependent process. Propofol's effects on sensory neurons may be clinically important and may contribute to peripheral sensitization to nociceptive stimuli in traumatized tissue.
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Santoni, Giorgio, Sara Caprodossi, Valerio Farfariello, Sonia Liberati, Angela Gismondi, and Consuelo Amantini. "Antioncogenic Effects of Transient Receptor Potential Vanilloid 1 in the Progression of Transitional Urothelial Cancer of Human Bladder." ISRN Urology 2012 (February 6, 2012): 1–11. http://dx.doi.org/10.5402/2012/458238.
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The progression of normal cells to a tumorigenic and metastatic state involves the accumulation of mutations in multiple key signaling proteins, encoded by oncogenes and tumor suppressor genes. Recently, members of the TRP channel family have been included in the oncogenic and tumor suppressor protein family. TRPM1, TRPM8, and TRPV6 are considered to be tumor suppressors and oncogenes in localized melanoma and prostate cancer, respectively. Herein, we focus our attention on the antioncogenic properties of TRPV1. Changes in TRPV1 expression occur during the development of transitional cell carcinoma (TCC) of human bladder. A progressive decrease in TRPV1 expression as the TCC stage increases triggers the development of a more aggressive gene phenotype and invasiveness. Finally, downregulation of TRPV1 represents a negative prognostic factor in TCC patients. The knowledge of the mechanism controlling TRPV1 expression might improve the diagnosis and new therapeutic strategies in bladder cancer.
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Everaerts, Wouter, Joris Vriens, Grzegorz Owsianik, Giovanni Appendino, Thomas Voets, Dirk De Ridder, and Bernd Nilius. "Functional characterization of transient receptor potential channels in mouse urothelial cells." American Journal of Physiology-Renal Physiology 298, no. 3 (March 2010): F692—F701. http://dx.doi.org/10.1152/ajprenal.00599.2009.
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The bladder urothelium is currently believed to be a sensory structure, contributing to mechano- and chemosensation in the bladder. Transient receptor potential (TRP) cation channels act as polymodal sensors and may underlie some of the receptive properties of urothelial cells. However, the exact TRP channel expression profile of urothelial cells is unclear. In this study, we have performed a systematic analysis of the molecular and functional expression of various TRP channels in mouse urothelium. Urothelial cells from control and trpv4−/− mice were isolated, cultured (12–48 h), and used for quantitative real-time PCR, immunocytochemistry, calcium imaging, and whole cell patch-clamp experiments. At the mRNA level, TRPV4, TRPV2, and TRPM7 were the most abundantly expressed TRP genes. Immunohistochemistry showed a clear expression of TRPV4 in the plasma membrane, whereas TRPV2 was more prominent in the cytoplasm. TRPM7 was detected in the plasma membrane as well as cytoplasmic vesicles. Calcium imaging and patch-clamp experiments using TRP channel agonists and antagonists provided evidence for the functional expression of TRPV4, TRPV2, and TRPM7 but not of TRPA1, TRPV1, and TRPM8. In conclusion, we have demonstrated functional expression of TRPV4, TRPV2, and TRPM7 in mouse urothelial cells. These channels may contribute to the (mechano)sensory function of the urothelial layer and represent potential targets for the treatment of bladder dysfunction.
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Ślęczkowska, Milena, Rowida Almomani, Margherita Marchi, Erika Salvi, Bianca T. A. de Greef, Maurice Sopacua, Janneke G. J. Hoeijmakers, et al. "Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy." International Journal of Molecular Sciences 23, no. 22 (November 15, 2022): 14095. http://dx.doi.org/10.3390/ijms232214095.
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Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes–next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.
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Zhao, Huan, and Steven M. Simasko. "Role of Transient Receptor Potential Channels in Cholecystokinin-Induced Activation of Cultured Vagal Afferent Neurons." Endocrinology 151, no. 11 (September 29, 2010): 5237–46. http://dx.doi.org/10.1210/en.2010-0504.
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Cholecystokinin (CCK), an endogenous brain-gut peptide, is released after food intake and promotes the process of satiation via activation of the vagus nerve. In vitro, CCK increases cytosolic calcium concentrations and produces membrane depolarization in a subpopulation of vagal afferent neurons. However, the specific mechanisms and ionic conductances that mediate these effects remain unclear. In this study we used calcium imaging, electrophysiological measurements, and single cell PCR analysis on cultured vagal afferent neurons to address this issue directly. A cocktail of blockers of voltage-dependent calcium channels (VDCC) failed to block CCK-induced calcium responses. In addition, SKF96365, a compound that blocks both VDCC and the C family of transient receptor potential (TRP) channels, also failed to prevent responses to CCK. Together these results suggest that CCK-induced calcium influx is not subsequent to the membrane depolarization. Ruthenium red, an inhibitor of the TRPV family and TRPA1, blocked both depolarizing responses to CCK and CCK-induced calcium increases, but had no effect on the KCl-induced calcium response. Selective block of TRPV1 and TRPA1 channels with SB366791 and HC030031, respectively, had minor effects on the CCK-induced response. Application of 2-aminoethoxydiphenyl borate, an activator of select TRPV channels but a blocker of several TRPC channels, either had no effect or enhanced the responses to CCK. Further, results from PCR experiments revealed a significant clustering of TRPV2-5 in neurons expressing CCK1 receptors. These observations demonstrate that CCK-induced increases in cytosolic calcium and membrane depolarization of vagal afferent neurons are likely mediated by TRPV channels, excluding TRPV1.
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Yu, Weiqun, Warren G. Hill, Gerard Apodaca, and Mark L. Zeidel. "Expression and distribution of transient receptor potential (TRP) channels in bladder epithelium." American Journal of Physiology-Renal Physiology 300, no. 1 (January 2011): F49—F59. http://dx.doi.org/10.1152/ajprenal.00349.2010.
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The urothelium is proposed to be a sensory tissue that responds to mechanical stress by undergoing dynamic membrane trafficking and neurotransmitter release; however, the molecular basis of this function is poorly understood. Transient receptor potential (TRP) channels are ideal candidates to fulfill such a role as they can sense changes in temperature, osmolarity, and mechanical stimuli, and several are reported to be expressed in the bladder epithelium. However, their complete expression profile is unknown and their cellular localization is largely undefined. We analyzed expression of all 33 TRP family members in mouse bladder and urothelium by RT-PCR and found 22 specifically expressed in the urothelium. Of the latter, 10 were chosen for closer investigation based on their known mechanosensory or membrane trafficking functions in other cell types. Western blots confirmed urothelial expression of TRPC1, TRPC4, TRPV1, TRPV2, TRPV4, TRPM4, TRPM7, TRPML1, and polycystins 1 and 2 (PKD1 and PKD2) proteins. We further defined the cellular and subcellular localization of all 10 TRP channels. TRPV2 and TRPM4 were prominently localized to the umbrella cell apical membrane, while TRPC4 and TRPV4 were identified on their abluminal surfaces. TRPC1, TRPM7, and TRPML1 were localized to the cytoplasm, while PKD1 and PKD2 were expressed on the apical and basolateral membranes of umbrella cells as well as in the cytoplasm. The cellular location of TRPV1 in the bladder has been debated, but colocalization with neuronal marker calcitonin gene-related peptide indicated clearly that it is present on afferent neurons that extend into the urothelium, but may not be expressed by the urothelium itself. These findings are consistent with the hypothesis that the urothelium acts as a sentinel and by expressing multiple TRP channels it is likely it can detect and presumably respond to a diversity of external stimuli and suggest that it plays an important role in urothelial signal transduction.
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Zheng, Jiaojiao, Fangyuan Liu, Sha Du, Mei Li, Tian Wu, Xuejing Tan, and Wei Cheng. "Mechanism for Regulation of Melanoma Cell Death via Activation of Thermo-TRPV4 and TRPV2." Journal of Oncology 2019 (February 7, 2019): 1–14. http://dx.doi.org/10.1155/2019/7362875.
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Background. Thermo-TRPs (temperature-sensitive transient receptor potential channels) belong to the TRP (transient receptor potential) channel superfamily. Emerging evidence implied that thermo-TRPs have been involved in regulation of cell fate in certain tumors. However, their distribution profiles and roles in melanoma remain incompletely understood. Methods. Western blot and digital PCR approaches were performed to identify the distribution profiles of six thermo-TRPs. MTT assessment was employed to detect cell viability. Flow cytometry was applied to test cell cycle and apoptosis. Calcium imaging was used to determine the function of channels. Five cell lines, including one normal human primary epidermal melanocytes and two human malignant melanoma (A375, G361) and two human metastatic melanoma (A2058, SK-MEL-3) cell lines, were chosen for this research. Results. In the present study, six thermo-TRPs including TRPV1/2/3/4, TRPA1, and TRPM8 were examined in human primary melanocytes and melanoma cells. We found that TRPV2/4, TRPA1, and TRPM8 exhibited ectopic distribution both in melanocytes and melanoma cells. Moreover, activation of TRPV2 and TRPV4 could lead to the decline of cell viability for melanoma A2058 and A375 cells. Subsequently, activation of TRPV2 by 2-APB (IC50 = 150 μM) induced cell necrosis in A2058 cells, while activation of TRPV4 by GSK1016790A (IC50 = 10 nM) enhanced apoptosis of A375 cells. Furthermore, TRPV4 mediated cell apoptosis of melanoma via phosphorylation of AKT and was involved in calcium regulation. Conclusion. Overall, our studies revealed that TRPV4 and TRPV2 mediated melanoma cell death via channel activation and characterized the mechanism of functional TRPV4 ion channel in regulating AKT pathway driven antitumor process. Thus, they may serve as potential biomarkers for the prognosis and are targeted for the therapeutic use in human melanoma.
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Nilius, Bernd, Joris Vriens, Jean Prenen, Guy Droogmans, and Thomas Voets. "TRPV4 calcium entry channel: a paradigm for gating diversity." American Journal of Physiology-Cell Physiology 286, no. 2 (February 2004): C195—C205. http://dx.doi.org/10.1152/ajpcell.00365.2003.
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The vanilloid receptor-1 (VR1, now TRPV1) was the founding member of a subgroup of cation channels within the TRP family. The TRPV subgroup contains six mammalian members, which all function as Ca2+ entry channels gated by a variety of physical and chemical stimuli. TRPV4, which displays 45% sequence identity with TRPV1, is characterized by a surprising gating promiscuity: it is activated by hypotonic cell swelling, heat, synthetic 4α-phorbols, and several endogenous substances including arachidonic acid (AA), the endocannabinoids anandamide and 2-AG, and cytochrome P-450 metabolites of AA, such as epoxyeicosatrienoic acids. This review summarizes data on TRPV4 as a paradigm of gating diversity in this subfamily of Ca2+ entry channels.
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Balemans, D., J. Aguilera-Lizarraga, M. V. Florens, P. Jain, A. Denadai-Souza, M. F. Viola, Y. A. Alpizar, et al. "Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 3 (March 1, 2019): G338—G349. http://dx.doi.org/10.1152/ajpgi.00116.2018.
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Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.
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Shabir, Saqib, William Cross, Lisa A. Kirkwood, Joanna F. Pearson, Peter A. Appleby, Dawn Walker, Ian Eardley, and Jennifer Southgate. "Functional expression of purinergic P2 receptors and transient receptor potential channels by the human urothelium." American Journal of Physiology-Renal Physiology 305, no. 3 (August 1, 2013): F396—F406. http://dx.doi.org/10.1152/ajprenal.00127.2013.
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In addition to its role as a physical barrier, the urothelium is considered to play an active role in mechanosensation. A key mechanism is the release of transient mediators that activate purinergic P2 receptors and transient receptor potential (TRP) channels to effect changes in intracellular Ca2+. Despite the implied importance of these receptors and channels in urothelial tissue homeostasis and dysfunctional bladder disease, little is known about their functional expression by the human urothelium. To evaluate the expression and function of P2X and P2Y receptors and TRP channels, the human ureter and bladder were used to separate urothelial and stromal tissues for RNA isolation and cell culture. RT-PCR using stringently designed primer sets was used to establish which P2 and TRP species were expressed at the transcript level, and selective agonists/antagonists were used to confirm functional expression by monitoring changes in intracellular Ca2+ and in a scratch repair assay. The results confirmed the functional expression of P2Y4 receptors and excluded nonexpressed receptors/channels (P2X1, P2X3, P2X6, P2Y6, P2Y11, TRPV5, and TRPM8), while a dearth of specific agonists confounded the functional validation of expressed P2X2, P2X4, P2Y1, P2Y2, TRPV2, TRPV3, TRPV6 and TRPM7 receptors/channels. Although a conventional response was elicited in control stromal-derived cells, the urothelial cell response to well-characterized TRPV1 and TRPV4 agonists/antagonists revealed unexpected anomalies. In addition, agonists that invoked an increase in intracellular Ca2+ promoted urothelial scratch repair, presumably through the release of ATP. The study raises important questions about the ligand selectivity of receptor/channel targets expressed by the urothelium. These pathways are important in urothelial tissue homeostasis, and this opens the possibility of selective drug targeting.
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Kiss, Fruzsina, Viktória Kormos, Éva Szőke, Angéla Kecskés, Norbert Tóth, Anita Steib, Árpád Szállási, et al. "Functional Transient Receptor Potential Ankyrin 1 and Vanilloid 1 Ion Channels Are Overexpressed in Human Oral Squamous Cell Carcinoma." International Journal of Molecular Sciences 23, no. 3 (February 8, 2022): 1921. http://dx.doi.org/10.3390/ijms23031921.
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Oral squamous cell carcinoma (OSCC) is a common cancer with poor prognosis. Transient Receptor Potential Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) receptors are non-selective cation channels expressed on primary sensory neurons and epithelial and immune cells. TRPV1 mRNA and immunopositivity, as well as TRPA1-like immunoreactivity upregulation, were demonstrated in OSCC, but selectivity problems with the antibodies still raise questions and their functional relevance is unclear. Therefore, here, we investigated TRPA1 and TRPV1 expressions in OSCC and analyzed their functions. TRPA1 and TRPV1 mRNA were determined by RNAscope in situ hybridization and qPCR. Radioactive 45Ca2+ uptake and ATP-based luminescence indicating cell viability were measured in PE/CA-PJ41 cells in response to the TRPA1 agonist allyl-isothiocyanate (AITC) and TRPV1 agonist capsaicin to determine receptor function. Both TRPA1 and TRPV1 mRNA are expressed in the squamous epithelium of the human oral mucosa and in PE/CA-PJ41 cells, and their expressions are significantly upregulated in OSCC compared to healthy mucosa. TRPA1 and TRPV1 activation (100 µM AITC, 100 nM capsaicin) induced 45Ca2+-influx into PE/CA-PJ41 cells. Both AITC (10 nM–5 µM) and capsaicin (100 nM–45 µM) reduced cell viability, reaching significant decrease at 100 nM AITC and 45 µM capsaicin. We provide the first evidence for the presence of non-neuronal TRPA1 receptor in the OSCC and confirm the expression of TRPV1 channel. These channels are functionally active and might regulate cancer cell viability.
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Toth, Balazs I., and Tamas Bíro. "TRP Channels and Pruritus." Open Pain Journal 6, no. 1 (March 8, 2013): 62–80. http://dx.doi.org/10.2174/1876386301306010062.
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Itch (pruritus) is one of the most often seen sensory phenomena in clinical practice. Recent neurophysiological findings proposed the existence of a novel pruriceptive system which includes a multitude of pruritogenic (itch-inducing) peripheral mediators, itch-selective pruriceptors, sensory afferent networks, spinal cord neurons, and certain central nervous system regions. In this review, we first introduce major features of the pruriceptive system. We then focus on defining the roles of transient receptor potential (TRP) ion channels in skin-coupled itch and provide compelling evidence that certain thermosensitive TRP channels (especially TRPV1, TRPV3, TRPV4, and TRPA1) are indeed key players in pruritus pathogenesis. Finally, we propose TRP-centered future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.
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Bousquet, Jean, Wienczyslawa Czarlewski, Torsten Zuberbier, Joaquim Mullol, Hubert Blain, Jean-Paul Cristol, Rafael De La Torre, et al. "Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19." International Archives of Allergy and Immunology 182, no. 4 (2021): 324–38. http://dx.doi.org/10.1159/000514204.
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In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.
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Payrits, Maja, Ádám Horváth, Tünde Biró-Sütő, János Erostyák, Géza Makkai, Éva Sághy, Krisztina Pohóczky, et al. "Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification." International Journal of Molecular Sciences 21, no. 14 (July 16, 2020): 5019. http://dx.doi.org/10.3390/ijms21145019.
Full textAbstract:
Transient Receptor Potential Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons and regulate nociceptor and inflammatory functions. Resolvins are endogenous lipid mediators. Resolvin D1 (RvD1) is described as a selective inhibitor of TRPA1-related postoperative and inflammatory pain in mice acting on the G protein-coupled receptor DRV1/GPR32. Resolvin D2 (RvD2) is a very potent TRPV1 and TRPA1 inhibitor in DRG neurons, and decreases inflammatory pain in mice acting on the GPR18 receptor, via TRPV1/TRPA1-independent mechanisms. We provided evidence that resolvins inhibited neuropeptide release from the stimulated sensory nerve terminals by TRPV1 and TRPA1 activators capsaicin (CAPS) and allyl-isothiocyanate (AITC), respectively. We showed that RvD1 and RvD2 in nanomolar concentrations significantly decreased TRPV1 and TRPA1 activation on sensory neurons by fluorescent calcium imaging and inhibited the CAPS- and AITC-evoked 45Ca-uptake on TRPV1- and TRPA1-expressing CHO cells. Since CHO cells are unlikely to express resolvin receptors, resolvins are suggested to inhibit channel opening through surrounding lipid raft disruption. Here, we proved the ability of resolvins to alter the membrane polarity related to cholesterol composition by fluorescence spectroscopy. It is concluded that targeting lipid raft integrity can open novel peripheral analgesic opportunities by decreasing the activation of nociceptors.
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Wilzopolski, Jenny, Manfred Kietzmann, Santosh K. Mishra, Holger Stark, Wolfgang Bäumer, and Kristine Rossbach. "TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch." Biomolecules 11, no. 8 (August 6, 2021): 1166. http://dx.doi.org/10.3390/biom11081166.
Full textAbstract:
Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.
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Makarieva, Tatyana N., Ekaterina K. Ogurtsova, Yuliya V. Korolkova, Yaroslav A. Andreev, Irina V. Mosharova, Ksenya M. Tabakmakher, Alla G. Guzii, et al. "Pulchranins B and C, New Acyclic Guanidine Alkaloids from the Far-Eastern Marine Sponge Monanchora Pulchra." Natural Product Communications 8, no. 9 (September 2013): 1934578X1300800. http://dx.doi.org/10.1177/1934578x1300800911.
Full textAbstract:
New marine natural products, pulchranins B and C (2 and 3), were isolated from the marine sponge Monanchora pulchra and their structures were established using NMR and MS analysis. Compounds 2 and 3 were moderately active as inhibitors of TRPV1 (EC50 value of 95 and 183 μM, respectively) and less potent against TRPV3 and TRPA1 receptors.
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Chung, Man-Kyo. "INTRODUCTION - Targeting TRP Channels for Pain Relief: TRPV1 and Beyond." Open Pain Journal 6, no. 1 (March 8, 2013): 8–9. http://dx.doi.org/10.2174/1876386301306010008.
Full textAbstract:
Management of chronic and pathological pain without incurring systemic side effects is a major medical challenge.Currently available drugs, such as non-steroidal anti-inflammatory drugs or opioid agonists, are efficacious through peripheral and central mechanisms. However, various complications and development of tolerance are serious problems. Other classes of drugs, such as anti-depressants and anti-convulsants, are often used for multiple pain syndromes. However, the efficacy of these drugs is commonly unsatisfactory, and their mechanism of action is not clear. For establishing novel, selective anti-hyperalgesic therapeutic approaches, targeted inhibition of pain-specific pathways or molecules would be ideal, and these approaches suggest straightforward strategies. A new era of exploring such “straightforward” approaches was opened with regard to peripheral nociceptors by the identification of the vanilloid receptor-1 (VR-1), which was designated transient receptor potential channel vanilloid subtype 1 (TRPV1). TRPV1 is a receptor for capsaicin, proton, and noxious heat. Capsaicin has long been known to be a natural compound capable of evoking an intense burning sensation and pain in human and experimental animals. It has been hypothesized that specific manipulation of TRPV1 may selectively relieve pain under injury or inflammatory conditions. Interfering with TRPV1 has been a central focus of these efforts during the 15 years following the cloning of TRPV1. Numerous pharmacological compounds have been developed targeting TRPV1. The characteristics and roles of TRPV1 have been rigorously studied using multiple approaches ranging from biophysical characterization to clinical trials in human subjects. Meanwhile, other members of the TRP channel family in addition to TRPV1 have been suggested to be also involved in nociception under pathophysiological conditions. These studies have identified targets in addition to TRPV1 as potential candidates for selective anti-hyperalgesic treatment free from complications. In this special issue of The Open Pain Journal, current knowledge regarding the roles of various TRP channels in pain is reviewed. Multiple scientists in academia and the pharmaceutical industry took part in this exciting project, and have shared their opinions regarding the prospects for relieving pain through targeting TRP channels. In the opening chapter, “Changes in TRP channels expression in painful conditions,” Bishnoi and Premkumar summarize the involvement of various members of the TRP channel family in nociception. The five following chapters are devoted to a discussion of the role of various TRP channels in specific pathological conditions. Blackshaw and colleagues review the evidence for the roles of “TRP channels in visceral pain.” They discuss the contribution of TRP channels, especially TRPV1, TRPV4, TRPA1, and TRPM8, to pain signaling in visceral systems in various visceral pathological models. The roles of “TRP channels in dental pain” are reviewed by Chung and Oh. The expression of various TRP channels in pulpal afferents and odontoblasts is summarized, and their potential contribution to dental pain by thermal and mechanical stimuli is discussed. In “The role of TRP channels in migraine,” Oxford and Hurley review the potential roles of TRP channels in a trigeminovascular system, their involvement in migraine attack, and recent clinical trials. Fernandes et al. discuss “TRP receptors in arthritis, gaining knowledge for translation from experimental models”. They review current knowledge pertaining to the therapeutic potential of TRP channels, primarily TRPV1 and TRPA1, for treating pain in osteoarthritis and other arthritic conditions. The roles of “Transient Receptor Potential channels in chemotherapy-induced neuropathy” are discussed by Nassini et al. In this chapter, the current understanding of the involvement of TRPV1, TRPV4, TRPM8, and TRPA1 in chemotherapy-induced neuropathy is highlighted. The next three chapters analyze the status of therapeutic approaches targeting TRPV1 using specific agonists and antagonists. In effects of topical capsaicin on cutaneous innervation: Implications for pain management Bley reviews the potential mechanisms of topical application of high concentrations of capsaicin to skin, and suggests pharmacokinetic and pharmacodynamic considerations of this therapy. Iadarola and colleagues discuss how site-specific administration of resiniferatoxin, an ultrapotent capsaicin analog, can overcome the limitations of topical capsaicin therapy, and they give an insight into the clinical trials using resiniferatoxin for permanent pain relief in cancer patients with intractable pain. Trevisani and Gatti discuss “TRPV1 antagonists as analgesic agents.” The authors review preclinical and clinical studies addressing the application of small molecule TRPV1 antagonists as anti-hyperalgesic thera-pies, and update current status of clinical trials
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Zhao, Huan, Leslie K. Sprunger, and Steven M. Simasko. "Expression of transient receptor potential channels and two-pore potassium channels in subtypes of vagal afferent neurons in rat." American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 2 (February 2010): G212—G221. http://dx.doi.org/10.1152/ajpgi.00396.2009.
Full textAbstract:
Vagal afferent neurons relay important information regarding the control of the gastrointestinal system. However, the ionic mechanisms that underlie vagal activation induced by sensory inputs are not completely understood. We postulate that transient receptor potential (TRP) channels and/or two-pore potassium (K2p) channels are targets for activating vagal afferents. In this study we explored the distribution of these channels in vagal afferents by quantitative PCR after a capsaicin treatment to eliminate capsaicin-sensitive neurons, and by single-cell PCR measurements in vagal afferent neurons cultured after retrograde labeling from the stomach or duodenum. We found that TRPC1/3/5/6, TRPV1-4, TRPM8, TRPA1, TWIK2, TRAAK, TREK1, and TASK1/2 were all present in rat nodose ganglia. Both lesion results and single-cell PCR results suggested that TRPA1 and TRPC1 were preferentially expressed in neurons that were either capsaicin sensitive or TRPV1 positive. Expression of TRPM8 varied dynamically after various manipulations, which perhaps explains the disparate results obtained by different investigators. Last, we also examined ion channel distribution with the A-type CCK receptor (CCK-RA) and found there was a significant preference for neurons that express TRAAK to also express CCK-RA, especially in gut-innervating neurons. These findings, combined with findings from prior studies, demonstrated that background conductances such as TRPC1, TRPA1, and TRAAK are indeed differentially distributed in the nodose ganglia, and not only do they segregate with specific markers, but the degree of overlap is also dependent on the innervation target.
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Szallasi, Arpad. "Preface by the Editor." Open Pain Journal 6, no. 1 (March 8, 2013): 7. http://dx.doi.org/10.2174/1876386301306010007.
Full textAbstract:
With over 600 reviews, Transient Receptor Potential (TRP) channels arguably represent today’s most extensively reviewed pharmacological targets. The literature on TRP channels is vast and still growing: it has exploded from a mere 21 papers in 1995 to over 2,000 in the past two years. In the past fifteen years, the field had shown spectacular progress. From the cloning of the vanilloid (capsaicin) recep a novel class of analgesic agents.tor TRPV1 in 1997 it has taken only a decade for the first small molecule TRPV1 antagonists to enter clinical trials as So why to add another review collection to this already overwhelming body of literature? First, new therapeutic tar-gets are emerging (e.g. TRPA1 and TRPV3) that look even more promising than TRPV1. Second, even the most studied TRP channel, TRPV1, continues to surprise. One might ar-gue that we are still at the beginning of the long and arduous road to obtain clinically useful analgesic drugs targeting TRP channels. It remains to be discovered if TRP channels are really Targets for Pain Relief, but it has already been clear that Bernd Nilius was right in calling TRP channels “Truly Remarkable Proteins.”
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Sakuta, Hiraki, Eri Nishihara, Takeshi Y. Hiyama, Chia-Hao Lin, and Masaharu Noda. "Nax signaling evoked by an increase in [Na+] in CSF induces water intake via EET-mediated TRPV4 activation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 311, no. 2 (August 1, 2016): R299—R306. http://dx.doi.org/10.1152/ajpregu.00352.2015.
Full textAbstract:
Water-intake behavior is under the control of brain systems that sense body fluid conditions at sensory circumventricular organs (sCVOs); however, the underlying mechanisms have not yet been elucidated in detail. Nax is a sodium (Na+) level sensor in the brain, and the transient receptor potential vanilloid (TRPV) channels TRPV1 and TRPV4 have been proposed to function as osmosensors. We herein investigated voluntary water intake immediately induced after an intracerebroventricular administration of a hypertonic NaCl solution in TRPV1-, TRPV4-, Na x-, and their double-gene knockout (KO) mice. The induction of water intake by TRPV1-KO mice was normal, whereas intake by TRPV4-KO and Na x-KO mice was significantly less than that by WT mice. Water intake by Na x /TRPV4-double KO mice was similar to that by the respective single KO mice. When TRPV4 activity was blocked with a specific antagonist HC-067047, water intake by WT mice was significantly reduced, whereas intake by TRPV4-KO and Na x-KO mice was not. Similar results were obtained with the administration of miconazole, which inhibits the biosynthesis of epoxyeicosatrienoic acids (EETs), endogenous agonists for TRPV4, from arachidonic acid (AA). Intracerebroventricular injection of hypertonic NaCl with AA or 5,6-EET restored water intake by Na x-KO mice to the wild-type level but not that by TRPV4-KO mice. These results suggest that the Na+ signal generated in Nax-positive glial cells leads to the activation of TRPV4-positive neurons in sCVOs to stimulate water intake by using EETs as gliotransmitters. Intracerebroventricular injection of equiosmolar hypertonic sorbitol solution induced small but significant water intake equally in all the genotypes, suggesting the presence of an unknown osmosensor in the brain.
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Saito, Shigeru, and Ryuzo Shingai. "Evolution of thermoTRP ion channel homologs in vertebrates." Physiological Genomics 27, no. 3 (December 2006): 219–30. http://dx.doi.org/10.1152/physiolgenomics.00322.2005.
Full textAbstract:
In mammalian thermosensation, nine temperature-sensitive ion channels that are activated by distinct temperature thresholds have been identified as thermosensors. These ion channels belong to the transient receptor potential (TRP) superfamily and are referred to as “thermoTRPs” (TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, TRPM4, TRPM5, TRPM8, and TRPA1). To elucidate the evolutionary processes of thermoTRPs, we conducted comprehensive searches for mammalian thermoTRP gene homologs in the draft genome sequences of chicken ( Gallus gallus), western clawed frog ( Xenopus tropicalis), zebrafish ( Danio rerio), and pufferfish ( Fugu rubripes). Newly identified homologs were compared with known thermoTRPs, and phylogenetic analyses were conducted. Our comparative analyses revealed that most of the mammalian thermo-TRP members already existed in the common ancestor of fishes and tetrapods. Tetrapods shared almost the same repertoire, except that the western clawed frog expanded TRPV4s (six copies) and TRPM8s (two copies), which were diversified considerably. Comparisons of nonsynonymous and synonymous substitution rates among TRPV4s suggested that one copy of the TRPV4 channel in the western clawed frog retained its original function, while the other copies diversified and obtained slightly different properties. In fish lineages, several members of thermo-TRPs have duplicated in the whole genome duplication occurred in the ancestral ray-finned fish; however, some of the copies have subsequently been lost. Furthermore, fishes do not possess the three members of thermoTRPs existed in mammals, e.g., thermoTRPs activated by noxious heat, warm, and cool temperatures. Our results suggest that thermosensation mechanisms have changed through vertebrate evolution with respect to thermosensor repertoires.
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Rhyu, Mee-Ra, Yiseul Kim, and Vijay Lyall. "Interactions between Chemesthesis and Taste: Role of TRPA1 and TRPV1." International Journal of Molecular Sciences 22, no. 7 (March 25, 2021): 3360. http://dx.doi.org/10.3390/ijms22073360.
Full textAbstract:
In addition to the sense of taste and olfaction, chemesthesis, the sensation of irritation, pungency, cooling, warmth, or burning elicited by spices and herbs, plays a central role in food consumption. Many plant-derived molecules demonstrate their chemesthetic properties via the opening of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) channels. TRPA1 and TRPV1 are structurally related thermosensitive cation channels and are often co-expressed in sensory nerve endings. TRPA1 and TRPV1 can also indirectly influence some, but not all, primary taste qualities via the release of substance P and calcitonin gene-related peptide (CGRP) from trigeminal neurons and their subsequent effects on CGRP receptor expressed in Type III taste receptor cells. Here, we will review the effect of some chemesthetic agonists of TRPA1 and TRPV1 and their influence on bitter, sour, and salt taste qualities.
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Mori, Noriyuki, Fuminori Kawabata, Shigenobu Matsumura, Hiroshi Hosokawa, Shigeo Kobayashi, Kazuo Inoue, and Tohru Fushiki. "Intragastric administration of allyl isothiocyanate increases carbohydrate oxidation via TRPV1 but not TRPA1 in mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300, no. 6 (June 2011): R1494—R1505. http://dx.doi.org/10.1152/ajpregu.00645.2009.
Full textAbstract:
The transient receptor potential (TRP) channel family is composed of a wide variety of cation-permeable channels activated polymodally by various stimuli and is implicated in a variety of cellular functions. Recent investigations have revealed that activation of TRP channels is involved not only in nociception and thermosensation but also in thermoregulation and energy metabolism. We investigated the effect of intragastric administration of TRP channel agonists on changes in energy substrate utilization of mice. Intragastric administration of allyl isothiocyanate (AITC; a typical TRPA1 agonist) markedly increased carbohydrate oxidation but did not affect oxygen consumption. To examine whether TRP channels mediate this increase in carbohydrate oxidation, we used TRPA1 and TRPV1 knockout (KO) mice. Intragastric administration of AITC increased carbohydrate oxidation in TRPA1 KO mice but not in TRPV1 KO mice. Furthermore, AITC dose-dependently increased intracellular calcium ion concentration in cells expressing TRPV1. These findings suggest that AITC might activate TRPV1 and that AITC increased carbohydrate oxidation via TRPV1.
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Nassini, Romina, Silvia Benemei, Camilla Fusi, Gabriela Trevisan, and Serena Materazzi. "Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy." Open Pain Journal 6, no. 1 (March 8, 2013): 127–36. http://dx.doi.org/10.2174/1876386301306010127.
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Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side effect of many chemotherapeuticdrugs, including platinum-based compounds (e.g., cisplatin and oxaliplatin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vincristine), and the first-in-class proteasome inhibitor, bortezomib. Among the various sensory symptoms of CIPN, paresthesia, dysesthesia, spontaneous pain, and mechanical and thermal hypersensitivity are prominent. Inflammation, oxidative stress, loss of intraepidermal nerve fibers, modifications of mitochondria, and various ion channels alterations are part of the several mechanisms contributing to CIPN. Because attempts to mitigate chemotherapeutic- induced acute neuronal hyperexcitability and the subsequent peripheral neuropathy have yielded unsatisfactory results, a more in-depth understanding of the mechanism(s) responsible for the neurotoxic action of anticancer drugs is required. Some members of the transient receptor potential (TRP) family of channels, as the TRPV1 and TRPV4 (vanilloid), TRPA1 (ankyrin) and TRPM8 (melastatin) are expressed on the plasma membrane of primary sensory neurons (nociceptors), where they are activated by an unprecedented series of physical and chemical stimuli. There is evidence that TRPV1, TRPV4, TRPA1 and TRPM8 are prominent contributors of mechanical and thermal hypersensitivity in models of CIPN. In particular, in vitro and in vivo studies have pointed out the unique role of TRPA1 and oxidative stress in the mechanism responsible for cold and mechanical hyperalgesia in rodent models of CIPN.
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Ceppa, Eugene, Fiore Cattaruzza, Victoria Lyo, Silvia Amadesi, Juan-Carlos Pelayo, Daniel P. Poole, Natalya Vaksman, et al. "Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 3 (September 2010): G556—G571. http://dx.doi.org/10.1152/ajpgi.00433.2009.
Full textAbstract:
The mechanisms of pancreatic pain, a cardinal symptom of pancreatitis, are unknown. Proinflammatory agents that activate transient receptor potential (TRP) channels in nociceptive neurons can cause neurogenic inflammation and pain. We report a major role for TRPV4, which detects osmotic pressure and arachidonic acid metabolites, and TRPA1, which responds to 4-hydroxynonenal and cyclopentenone prostaglandins, in pancreatic inflammation and pain in mice. Immunoreactive TRPV4 and TRPA1 were detected in pancreatic nerve fibers and in dorsal root ganglia neurons innervating the pancreas, which were identified by retrograde tracing. Agonists of TRPV4 and TRPA1 increased intracellular Ca2+ concentration ([Ca2+]i) in these neurons in culture, and neurons also responded to the TRPV1 agonist capsaicin and are thus nociceptors. Intraductal injection of TRPV4 and TRPA1 agonists increased c-Fos expression in spinal neurons, indicative of nociceptor activation, and intraductal TRPA1 agonists also caused pancreatic inflammation. The effects of TRPV4 and TRPA1 agonists on [Ca2+]i, pain and inflammation were markedly diminished or abolished in trpv4 and trpa1 knockout mice. The secretagogue cerulein induced pancreatitis, c-Fos expression in spinal neurons, and pain behavior in wild-type mice. Deletion of trpv4 or trpa1 suppressed c-Fos expression and pain behavior, and deletion of trpa1 attenuated pancreatitis. Thus TRPV4 and TRPA1 contribute to pancreatic pain, and TRPA1 also mediates pancreatic inflammation. Our results provide new information about the contributions of TRPV4 and TRPA1 to inflammatory pain and suggest that channel antagonists are an effective therapy for pancreatitis, when multiple proinflammatory agents are generated that can activate and sensitize these channels.
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Wen, Jiliang, Shulu Zu, Zhenghao Chen, Stephanie L. Daugherty, William C. de Groat, Yuqiang Liu, Mingzhen Yuan, Guanghui Cheng, and Xiulin Zhang. "Reduced bladder responses to capsaicin and GSK-1016790A in retired-breeder female rats with diminished volume sensitivity." American Journal of Physiology-Renal Physiology 315, no. 5 (November 1, 2018): F1217—F1227. http://dx.doi.org/10.1152/ajprenal.00198.2018.
Full textAbstract:
Literature documents an age-related reduction of bladder sensory function. Transient receptor potential vanilloid (TRPV)1 or TRPV4 channels have been implicated in bladder mechanotransduction. To investigate contributions of TRPV1 or TRPV4 to the age-related reduction of bladder sensory function, bladder responses to capsaicin (CAP; TRPV1 agonist) and GSK-1016790A (GSK; TRPV4 agonist) in retired breeder (RB; 12–15 mo) and young adult (2–3 mo) female rats were compared using multiple methods. Metabolic cage and continuous infusion cystometry [cystometrogram (CMG)] recordings revealed that RB rats exhibit larger bladder capacity and lower voiding frequency. RB rats also have a greater intravesical pressure threshold for micturition; however, the voiding contraction strength was equivalent to that in young rats. CAP (1 μM) or GSK (20 nM) administered intravesically evoked smaller changes in all CMG parameters in RB rats. In vitro, CAP (1 μM) or GSK (20 nM) evoked smaller enhancement of bladder strip contractions, while the muscarinic receptor agonist carbachol (at 100, 300, and 1,000 nM) elicited greater amplitude contractions in RB rats. Patch-clamp recording revealed smaller CAP (100 nM) induced inward currents in bladder primary sensory neurons, and Ca2+ imaging revealed smaller GSK (20 nM) evoked increases in intracellular Ca2+ concentration in urothelial cells in RB rats. These results suggest that RB rats have a decreased bladder sensory function commonly observed in elderly women, and could be used as an animal model to study the underling mechanisms. Reduced functional expression of TRPV1 in bladder afferents or reduced functional expression of urothelial TRPV4 may be associated with the diminished sensory function.
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Ghosh, Monica, Igor A. Schepetkin, Gulmira Özek, Temel Özek, Andrei I. Khlebnikov, Derek S. Damron, and Mark T. Quinn. "Essential Oils from Monarda fistulosa: Chemical Composition and Activation of Transient Receptor Potential A1 (TRPA1) Channels." Molecules 25, no. 21 (October 22, 2020): 4873. http://dx.doi.org/10.3390/molecules25214873.
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Little is known about the pharmacological activity of Monarda fistulosa L. essential oils. To address this issue, we isolated essential oils from the flowers and leaves of M. fistulosa and analyzed their chemical composition. We also analyzed the pharmacological effects of M. fistulosa essential oils on transient receptor potential (TRP) channel activity, as these channels are known targets of various essential oil constituents. Flower (MEOFl) and leaf (MEOLv) essential oils were comprised mainly of monoterpenes (43.1% and 21.1%) and oxygenated monoterpenes (54.8% and 77.7%), respectively, with a high abundance of monoterpene hydrocarbons, including p-cymene, γ-terpinene, α-terpinene, and α-thujene. Major oxygenated monoterpenes of MEOFl and MEOLv included carvacrol and thymol. Both MEOFl and MEOLv stimulated a transient increase in intracellular free Ca2+ concentration ([Ca2+]i) in TRPA1 but not in TRPV1 or TRPV4-transfected cells, with MEOLv being much more effective than MEOFl. Furthermore, the pure monoterpenes carvacrol, thymol, and β-myrcene activated TRPA1 but not the TRPV1 or TRPV4 channels, suggesting that these compounds represented the TRPA1-activating components of M. fistulosa essential oils. The transient increase in [Ca2+]i induced by MEOFl/MEOLv, carvacrol, β-myrcene, and thymol in TRPA1-transfected cells was blocked by a selective TRPA1 antagonist, HC-030031. Although carvacrol and thymol have been reported previously to activate the TRPA1 channels, this is the first report to show that β-myrcene is also a TRPA1 channel agonist. Finally, molecular modeling studies showed a substantial similarity between the docking poses of carvacrol, thymol, and β-myrcene in the binding site of human TRPA1. Thus, our results provide a cellular and molecular basis to explain at least part of the therapeutic properties of these essential oils, laying the foundation for prospective pharmacological studies involving TRP ion channels.
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Li, Fengxian, Changxiong J. Guo, Cheng-Chiu Huang, Guang Yu, Sarah M. Brown, Shiyuan Xu, and Qin Liu. "Transient Receptor Potential A1 Activation Prolongs Isoflurane Induction Latency and Impairs Respiratory Function in Mice." Anesthesiology 122, no. 4 (April 1, 2015): 768–75. http://dx.doi.org/10.1097/aln.0000000000000607.
Full textAbstract:
Abstract Background: Isoflurane is a potent volatile anesthetic; however, it evokes airway irritation and neurogenic constriction through transient receptor potential (TRP) A1 channels and sensitizes TRPV1 channels, which colocalizes with TRPA1 in most of the vagal C-fibers innervating the airway. However, little is known about the precise effects of these two channels on the respiratory function during isoflurane anesthesia. Methods: By using a rodent behavioral model and whole-body plethysmograph, the authors examined the response of Trpa1−/− and Trpv1−/− mice to isoflurane anesthesia and monitored their respiratory functions during anesthesia. Results: This study showed that Trpa1−/− mice (n = 9), but not Trpv1−/− mice (n = 11), displayed a shortened induction latency compared with wild-type mice (n = 10) during isoflurane anesthesia (33 ± 2.0 s in wild-type and 33 ± 3.8 s in Trpv1−/−vs. 17 ± 1.8 in Trpa1−/− at 2.2 minimum alveolar concentrations). By contrast, their response to the nonpungent volatile anesthetic sevoflurane is indistinguishable from wild-type mice (24 ± 3.6 s in wild-type vs. 26 ± 1.0 s in Trpa1−/− at 2.4 minimum alveolar concentrations). The authors discovered that Trpa1−/− mice inhaled more anesthetic but maintained better respiratory function. Further respiration pattern analysis revealed that isoflurane triggered nociceptive reflexes and led to prolonged resting time between breaths during isoflurane induction as well as decreased dynamic pulmonary compliance, an indicator of airway constriction, throughout isoflurane anesthesia in wild-type and Trpv1−/− mice, but not in Trpa1−/− mice. Conclusion: Activation of TRPA1 by isoflurane negatively affects anesthetic induction latency by altering respiratory patterns and impairing pulmonary compliance.
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Jeske, Nathaniel A., Amol M. Patwardhan, Nikita Gamper, Theodore J. Price, Armen N. Akopian, and Kenneth M. Hargreaves. "Cannabinoid WIN 55,212-2 Regulates TRPV1 Phosphorylation in Sensory Neurons." Journal of Biological Chemistry 281, no. 43 (September 5, 2006): 32879–90. http://dx.doi.org/10.1074/jbc.m603220200.
Full textAbstract:
Cannabinoids are known to have multiple sites of action in the nociceptive system, leading to reduced pain sensation. However, the peripheral mechanism(s) by which this phenomenon occurs remains an issue that has yet to be resolved. Because phosphorylation of TRPV1 (transient receptor potential subtype V1) plays a key role in the induction of thermal hyperalgesia in inflammatory pain models, we evaluated whether the cannabinoid agonist WIN 55,212-2 (WIN) regulates the phosphorylation state of TRPV1. Here, we show that treatment of primary rat trigeminal ganglion cultures with WIN led to dephosphorylation of TRPV1, specifically at threonine residues. Utilizing Chinese hamster ovary cell lines, we demonstrate that Thr144 and Thr370 were dephosphorylated, leading to desensitization of the TRPV1 receptor. This post-translational modification occurred through activation of the phosphatase calcineurin (protein phosphatase 2B) following WIN treatment. Furthermore, knockdown of TRPA1 (transient receptor potential subtype A1) expression in sensory neurons by specific small interfering RNA abolished the WIN effect on TRPV1 dephosphorylation, suggesting that WIN acts through TRPA1. We also confirm the importance of TRPA1 in WIN-induced dephosphorylation of TRPV1 in Chinese hamster ovary cells through targeted expression of one or both receptor channels. These results imply that the cannabinoid WIN modulates the sensitivity of sensory neurons to TRPV1 activation by altering receptor phosphorylation. In addition, our data could serve as a useful strategy in determining the potential use of certain cannabinoids as peripheral analgesics.
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Wu, Shaw-wen, Jonathan E. M. Lindberg, and James H. Peters. "Genetic and pharmacological evidence for low-abundance TRPV3 expression in primary vagal afferent neurons." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 310, no. 9 (May 1, 2016): R794—R805. http://dx.doi.org/10.1152/ajpregu.00366.2015.
Full textAbstract:
Primary vagal afferent neurons express a multitude of thermosensitive ion channels. Within this family of ion channels, the heat-sensitive capsaicin receptor (TRPV1) greatly influences vagal afferent signaling by determining the threshold for action-potential initiation at the peripheral endings, while controlling temperature-sensitive forms of glutamate release at central vagal terminals. Genetic deletion of TRPV1 does not completely eliminate these temperature-dependent effects, suggesting involvement of additional thermosensitive ion channels. The warm-sensitive, calcium-permeable, ion channel TRPV3 is commonly expressed with TRPV1; however, the extent to which TRPV3 is found in vagal afferent neurons is unknown. Here, we begin to characterize the genetic and functional expression of TRPV3 in vagal afferent neurons using molecular biology (RT-PCR and RT-quantitative PCR) in whole nodose and isolated neurons and fluorescent calcium imaging on primary cultures of nodose ganglia neurons. We confirmed low-level TRPV3 expression in vagal afferent neurons and observed direct activation with putative TRPV3 agonists eugenol, ethyl vanillin (EVA), and farnesyl pyrophosphate (FPP). Agonist activation stimulated neurons also containing TRPV1 and was blocked by ruthenium red. FPP sensitivity overlapped with EVA and eugenol but represented the smallest percentage of vagal afferent neurons, and it was the only agonist that did not stimulate neurons from TRPV3−/−1 mice, suggesting FPP has the highest selectivity. Further, FPP was predictive of enhanced responses to capsaicin, EVA, and eugenol in rats. From our results, we conclude TRPV3 is expressed in a discrete subpopulation of vagal afferent neurons and may contribute to vagal afferent signaling either directly or in combination with TRPV1.