scholarly journals TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus

2015 ◽  
Vol 308 (6) ◽  
pp. G489-G496 ◽  
Author(s):  
Xiaoyun Yu ◽  
Youtian Hu ◽  
Fei Ru ◽  
Marian Kollarik ◽  
Bradley J. Undem ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Sensory Transduction ◽  
Dependent Manner ◽  
Preferential Expression ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor

Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes. TRPM8 agonist WS-12-induced responses were first determined in nodose and jugular neurons by calcium imaging and then investigated by whole cell patch-clamp recordings in Dil-labeled esophageal nodose and jugular neurons. Extracellular single-unit recordings were performed in nodose and jugular C fiber neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. TRPM8 mRNA expression was determined by single neuron RT-PCR in Dil-labeled esophageal nodose and jugular neurons. The TRPM8 agonist WS-12 elicited calcium influx in a subpopulation of jugular but not nodose neurons. WS-12 activated outwardly rectifying currents in esophageal Dil-labeled jugular but not nodose neurons in a dose-dependent manner, which could be inhibited by the TRPM8 inhibitor AMTB. WS-12 selectively evoked action potential discharges in esophageal jugular but not nodose C fibers. Consistently, TRPM8 transcripts were highly expressed in esophageal Dil-labeled TRPV1-positive jugular neurons. In summary, the present study demonstrated a preferential expression and function of TRPM8 in esophageal vagal jugular but not nodose neurons and C fiber subtypes. This provides a distinctive role of TRPM8 in esophageal sensory transduction and may lead to a better understanding of the mechanisms of esophageal sensation and nociception.

scholarly journals Mechanisms of the adenosine A2Areceptor-induced sensitization of esophageal C fibers

2016 ◽  
Vol 310 (3) ◽  
pp. G215-G223 ◽  
Author(s):  
M. Brozmanova ◽  
L. Mazurova ◽  
F. Ru ◽  
M. Tatar ◽  
Y. Hu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Mechanical Response ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Receptor Potential ◽  
P2x Receptor ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor ◽  
Stimulation Of

Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2Areceptor. Here we addressed the hypothesis that stimulation of the adenosine A2Areceptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2Areceptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10–60 mmHg) in a concentration-dependent fashion (1–100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2Aantagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,β-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031 . Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2Areceptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

scholarly journals Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release

2015 ◽  
Vol 112 (11) ◽  
pp. E1363-E1372 ◽  
Author(s):  
Katharina Held ◽  
Tatjana Kichko ◽  
Katrien De Clercq ◽  
Hugo Klaassen ◽  
Rieta Van Bree ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Sensory Nerve ◽  
Somatosensory System ◽  
Receptor Potential ◽  
Intradermal Injection ◽  
Dependent Manner ◽  
Noxious Heat ◽  
Isolated Pancreatic Islets ◽  
Transient Receptor

Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin gene-related peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.

Menthol suppresses laryngeal C-fiber hypersensitivity to cigarette smoke in a rat model of gastroesophageal reflux disease: the role of TRPM8

2015 ◽  
Vol 118 (5) ◽  
pp. 635-645 ◽  
Author(s):  
Bi-Yu Liu ◽  
Yu-Jung Lin ◽  
Hung-Fu Lee ◽  
Ching-Yin Ho ◽  
Ting Ruan ◽  
...  
Keyword(s):  
Gastroesophageal Reflux Disease ◽  
Gastroesophageal Reflux ◽  
Cigarette Smoke ◽  
Reflux Disease ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
C Fibers ◽  
C Fiber ◽  
Trpv1 Antagonist ◽  
Transient Receptor

Patients with gastroesophageal reflux disease (GERD) display enhanced laryngeal reflex reactivity to stimuli that may be due to sensitization of the laryngeal C-fibers by acid and pepsin. Menthol, a ligand of transient receptor potential melastatin-8 (TRPM8), relieves throat irritation. However, the possibility that GERD induces laryngeal C-fiber hypersensitivity to cigarette smoke (CS) and that menthol suppresses this event has not been investigated. We delivered CS into functionally isolated larynxes of 160 anesthetized rats. Laryngeal pH 5-pepsin treatment, but not pH 5-denatured pepsin, augmented the apneic response to CS, which was blocked by denervation or perineural capsaicin treatment (a procedure that blocks the conduction of C fibers) of the superior laryngeal nerves. This augmented apnea was partially attenuated by capsazepine [an transient receptor potential vanilloid 1 (TRPV1) antagonist], SB-366791 (a TRPV1 antagonist), and HC030031 [a transient receptor potential ankyrin 1 (TRPA1) antagonist] and was completely prevented by a combination of TRPV1 and TRPA1 antagonists. Local application of menthol significantly suppressed the augmented apnea and this effect was reversed by pretreatment with AMTB (a TRPM8 antagonist). Our electrophysiological studies consistently revealed that laryngeal pH 5-pepsin treatment increased the sensitivity of laryngeal C-fibers to CS. Likewise, menthol suppressed this laryngeal C-fiber hypersensitivity and its effect could be reversed by pretreatment with AMTB. Our results suggest that laryngeal pH 5-pepsin treatment increases sensitivity to CS of both TRPV1 and TRPA1, which are presumably located at the terminals of laryngeal C-fibers. This sensory sensitization leads to enhanced laryngeal reflex reactivity and augmentation of the laryngeal C-fiber responses to CS, which can be suppressed by menthol acting via TRPM8.

scholarly journals Capsazepine decreases corneal pain syndrome in severe dry eye disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Darine Fakih ◽  
Adrian Guerrero-Moreno ◽  
Christophe Baudouin ◽  
Annabelle Réaux-Le Goazigo ◽  
Stéphane Mélik Parsadaniantz
Keyword(s):  
In Situ Hybridization ◽  
Inflammatory Pain ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Eye Disease ◽  
Ocular Pain ◽  
Trpv1 Antagonist ◽  
Transient Receptor

Abstract Background Dry eye disease (DED) is a multifactorial disease of the ocular surface accompanied by neurosensory abnormalities. Here, we evaluated the effectiveness of transient receptor potential vanilloid-1 (TRPV1) blockade to alleviate ocular pain, neuroinflammation, and anxiety-like behavior associated with severe DED. Methods Chronic DED was induced by unilateral excision of the Harderian and extraorbital lacrimal glands of adult male mice. Investigations were conducted at 21 days after surgery. The mRNA levels of TRPV1, transient receptor potential ankyrin-1 (TRPA1), and acid-sensing ion channels 1 and 3 (ASIC1 and ASIC3) in the trigeminal ganglion (TG) were evaluated by RNAscope in situ hybridization. Multi-unit extracellular recording of ciliary nerve fiber activity was used to monitor spontaneous and stimulated (cold, heat, and acid) corneal nerve responsiveness in ex vivo eye preparations. DED mice received topical instillations of the TRPV1 antagonist (capsazepine) twice a day for 2 weeks from d7 to d21 after surgery. The expression of genes involved in neuropathic and inflammatory pain was evaluated in the TG using a global genomic approach. Chemical and mechanical corneal nociception and spontaneous ocular pain were monitored. Finally, anxiety-like behaviors were assessed by elevated plus maze and black and white box tests. Results First, in situ hybridization showed DED to trigger upregulation of TRPV1, TRPA1, ASIC1, and ASIC3 mRNA in the ophthalmic branch of the TG. DED also induced overexpression of genes involved in neuropathic and inflammatory pain in the TG. Repeated instillations of capsazepine reduced corneal polymodal responsiveness to heat, cold, and acidic stimulation in ex vivo eye preparations. Consistent with these findings, chronic capsazepine instillation inhibited the upregulation of genes involved in neuropathic and inflammatory pain in the TG of DED animals and reduced the sensation of ocular pain, as well as anxiety-like behaviors associated with severe DED. Conclusion These data provide novel insights on the effectiveness of TRPV1 antagonist instillation in alleviating abnormal corneal neurosensory symptoms induced by severe DED, opening an avenue for the repositioning of this molecule as a potential analgesic treatment for patients suffering from chronic DED.

scholarly journals Potentiation of TRPC5 by Protons

2007 ◽  
Vol 282 (46) ◽  
pp. 33868-33878 ◽  
Author(s):  
Marcus Semtner ◽  
Michael Schaefer ◽  
Olaf Pinkenburg ◽  
Tim D. Plant
Keyword(s):  
Phospholipase C ◽  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
High Sensitivity ◽  
Transient Receptor Potential Channel ◽  
Extracellular Ph ◽  
Dependent Manner ◽  
Open Probability ◽  
Transient Receptor

Mammalian members of the classical transient receptor potential channel subfamily (TRPC) are Ca2+-permeable cation channels involved in receptor-mediated increases in intracellular Ca2+. TRPC4 and TRPC5 form a group within the TRPC subfamily and are activated in a phospholipase C-dependent manner by an unidentified messenger. Unlike most other Ca2+-permeable channels, TRPC4 and -5 are potentiated by micromolar concentrations of La3+ and Gd3+. This effect results from an action of the cations at two glutamate residues accessible from the extracellular solution. Here, we show that TRPC4 and -5 respond to changes in extracellular pH. Lowering the pH increased both G protein-activated and spontaneous TRPC5 currents. Both effects were already observed with small reductions in pH (from 7.4 to 7.0) and increased up to pH 6.5. TRPC4 was also potentiated by decreases in pH, whereas TRPC6 was only inhibited, with a pIC50 of 5.7. Mutation of the glutamate residues responsible for lanthanoid sensitivity of TRPC5 (E543Q and E595Q) modified the potentiation of TRPC5 by acid. Further evidence for a similarity in the actions of lanthanoids and H+ on TRPC5 is the reduction in single channel conductance and dramatic increase in channel open probability in the presence of either H+ or Gd3+ that leads to larger integral currents. In conclusion, the high sensitivity of TRPC5 to H+ indicates that, in addition to regulation by phospholipase C and other factors, the channel may act as a sensor of pH that links decreases in extracellular pH to Ca2+ entry and depolarization.

scholarly journals TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases

2015 ◽  
Vol 309 (5) ◽  
pp. F393-F397 ◽  
Author(s):  
Daria V. Ilatovskaya ◽  
Alexander Staruschenko
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Kidney Diseases ◽  
Critical Role ◽  
Receptor Potential ◽  
Calcium Flux ◽  
Calcium Handling ◽  
Podocyte Injury ◽  
Trpc6 Channel ◽  
Transient Receptor

Podocytes (terminally differentiated epithelial cells of the glomeruli) play a key role in the maintenance of glomerular structure and permeability and in the incipiency of various renal abnormalities. Injury to podocytes is considered a major contributor to the development of kidney disease as their loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium handling; excessive calcium influx in these cells may result in the effacement of foot processes, apoptosis, and subsequent glomeruli damage. One of the key proteins responsible for calcium flux in the podocytes is transient receptor potential cation channel, subfamily C, member 6 (TRPC6); a gain-of-function mutation in TRPC6 has been associated with the onset of the familial forms of focal segmental glomerulosclerosis (FSGS). Recent data also revealed a critical role of this channel in the onset of diabetic nephropathy. Therefore, major efforts of the research community have been recently dedicated to unraveling the TRPC6-dependent effects in the initiation of podocyte injury. This mini-review focuses on the TRPC6 channel in podocytes and colligates recent data in an attempt to shed some light on the mechanisms underlying the pathogenesis of TRPC6-mediated glomeruli damage and its potential role as a therapeutic target for the treatment of chronic kidney diseases.

scholarly journals The Na+/Ca2+ Exchanger Inhibitor, KB-R7943, Blocks a Nonselective Cation Channel Implicated in Chemosensory Transduction

2009 ◽  
Vol 101 (3) ◽  
pp. 1151-1159 ◽  
Author(s):  
A. Pezier ◽  
Y. V. Bobkov ◽  
B. W. Ache
Keyword(s):  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
Trpc Channels ◽  
Dependent Manner ◽  
Open Probability ◽  
Olfactory Transduction ◽  
Voltage Dependent ◽  
Chemosensory Transduction ◽  
Transient Receptor

The mechanism(s) of olfactory transduction in invertebrates remains to be fully understood. In lobster olfactory receptor neurons (ORNs), a nonselective sodium-gated cation (SGC) channel, a presumptive transient receptor potential (TRP)C channel homolog, plays a crucial role in olfactory transduction, at least in part by amplifying the primary transduction current. To better determine the functional role of the channel, it is important to selectively block the channel independently of other elements of the transduction cascade, causing us to search for specific pharmacological blockers of the SGC channel. Given evidence that the Na+/Ca2+ exchange inhibitor, KB-R7943, blocks mammalian TRPC channels, we studied this probe as a potential blocker of the lobster SGC channel. KB-R7943 reversibly blocked the SGC current in both inside- and outside-out patch recordings in a dose- and voltage-dependent manner. KB-R7943 decreased the channel open probability without changing single channel amplitude. KB-R7943 also reversibly and in a dose-dependent manner inhibited both the odorant-evoked discharge of lobster ORNs and the odorant-evoked whole cell current. Our findings strongly imply that KB-R7943 potently blocks the lobster SGC channel and likely does so directly and not through its ability to block the Na+/Ca2+ exchanger.

scholarly journals The Role of Ca2+-NFATc1 Signaling and Its Modulation on Osteoclastogenesis

2020 ◽  
Vol 21 (10) ◽  
pp. 3646
Author(s):  
Jung Yun Kang ◽  
Namju Kang ◽  
Yu-Mi Yang ◽  
Jeong Hee Hong ◽  
Dong Min Shin
Keyword(s):  
Bone Loss ◽  
Calcium Signaling ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Osteoclast Differentiation ◽  
Receptor Potential ◽  
Cytosolic Calcium ◽  
Transient Receptor Potential Channels ◽  
Potential Channels ◽  
Transient Receptor

The increasing of intracellular calcium concentration is a fundamental process for mediating osteoclastogenesis, which is involved in osteoclastic bone resorption. Cytosolic calcium binds to calmodulin and subsequently activates calcineurin, leading to NFATc1 activation, a master transcription factor required for osteoclast differentiation. Targeting the various activation processes in osteoclastogenesis provides various therapeutic strategies for bone loss. Diverse compounds that modulate calcium signaling have been applied to regulate osteoclast differentiation and, subsequently, attenuate bone loss. Thus, in this review, we summarized the modulation of the NFATc1 pathway through various compounds that regulate calcium signaling and the calcium influx machinery. Furthermore, we addressed the involvement of transient receptor potential channels in osteoclastogenesis.

scholarly journals The nonselective cation channel TRPV4 inhibits angiotensin II receptors

2020 ◽  
Vol 295 (29) ◽  
pp. 9986-9997
Author(s):  
Nicholas W. Zaccor ◽  
Charlotte J. Sumner ◽  
Solomon H. Snyder
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Trp Channel ◽  
Luciferase Assay ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

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