Localization of TRPA1 channels and characterization of TRPA1 mediated responses in dural and pial arteries in vivo after intracarotid infusion of Na2S

Cephalalgia ◽  
2020 ◽  
Vol 40 (12) ◽  
pp. 1310-1320
Author(s):  
Anna Koldbro Hansted ◽  
Lars Jørn Jensen ◽  
Jes Olesen ◽  
Inger Jansen-Olesen
Keyword(s):  
Dura Mater ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Nerve Fibers ◽  
Pial Arteries ◽  
Cranial Window ◽  
Cgrp Receptor Antagonist ◽  
Transient Receptor ◽  
Channel Dependent

Background The Transient Receptor Potential Ankyrin 1 (TRPA1) channel might play a role in migraine. However, different mechanisms for this have been suggested. The purpose of our study was to investigate the localization and significance of TRPA1 channels in rat pial and dural arteries. Methods Immunofluorescence microscopy was used to localize TRPA1 channels in dural arteries, pial arteries, dura mater and trigeminal ganglion. The genuine closed cranial window model was used to examine the effect of Na2S, a donor of the TRPA1 channel opener H2S, on the diameter of pial and dural arteries. Further, we performed blocking experiments with TRPA1 antagonist HC-030031, calcitonin gene-related peptide (CGRP) receptor antagonist olcegepant and KCa3.1 channel blocker TRAM-34. Results TRPA1 channels were localized to the endothelium of both dural and pial arteries and in nerve fibers in dura mater. Further, we found TRPA1 expression in the membrane of trigeminal ganglia neuronal cells, some of them also staining for CGRP. Na2S caused dilation of both dural and pial arteries. In dural arteries, this was inhibited by HC-030031 and olcegepant. In pial arteries, the dilation was inhibited by TRAM-34, suggesting involvement of the KCa3.1 channel. Conclusion Na2S causes a TRPA1- and CGRP-dependent dilation of dural arteries and a KCa3.1 channel-dependent dilation of pial arteries in rats.

scholarly journals A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Magdalena Nikolaeva-Koleva ◽  
Laura Butron ◽  
Sara González-Rodríguez ◽  
Isabel Devesa ◽  
Pierluigi Valente ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Primary Cultures ◽  
Receptor Potential ◽  
Neuronal Firing ◽  
In Vivo Model ◽  
Drg Neurons ◽  
Trpv1 Channels ◽  
Soft Drug ◽  
Transient Receptor

AbstractTRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.

scholarly journals 4-Oxo-2-nonenal (4-ONE): Evidence of Transient Receptor Potential Ankyrin 1-Dependent and -Independent Nociceptive and Vasoactive Responses In Vivo

2011 ◽  
Vol 337 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Rabea Graepel ◽  
Elizabeth S. Fernandes ◽  
Aisah A. Aubdool ◽  
David A. Andersson ◽  
Stuart Bevan ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor

scholarly journals Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance

2014 ◽  
Vol 306 (4) ◽  
pp. H574-H584 ◽  
Author(s):  
Jack Rubinstein ◽  
Valerie M. Lasko ◽  
Sheryl E. Koch ◽  
Vivek P. Singh ◽  
Vinicius Carreira ◽  
...  
Keyword(s):  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Transient Receptor ◽  
Systolic And Diastolic Function ◽  
Myocyte Contractility

Transient receptor potential cation channels have been implicated in the regulation of cardiovascular function, but only recently has our laboratory described the vanilloid-2 subtype (TRPV2) in the cardiomyocyte, though its exact mechanism of action has not yet been established. This study tests the hypothesis that TRPV2 plays an important role in regulating myocyte contractility under physiological conditions. Therefore, we measured cardiac and vascular function in wild-type and TRPV2−/− mice in vitro and in vivo and found that TRPV2 deletion resulted in a decrease in basal systolic and diastolic function without affecting loading conditions or vascular tone. TRPV2 stimulation with probenecid, a relatively selective TRPV2 agonist, caused an increase in both inotropy and lusitropy in wild-type mice that was blunted in TRPV2−/− mice. We examined the mechanism of TRPV2 inotropy/lusitropy in isolated myocytes and found that it modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ loading. We show that the activity of this channel is necessary for normal cardiac function and that there is increased contractility in response to agonism of TRPV2 with probenecid.

scholarly journals TRPM4 Channels Couple Purinergic Receptor Mechanoactivation and Myogenic Tone Development in Cerebral Parenchymal Arterioles

2014 ◽  
Vol 34 (10) ◽  
pp. 1706-1714 ◽  
Author(s):  
Yao Li ◽  
Rachael L Baylie ◽  
Matthew J Tavares ◽  
Joseph E Brayden
Keyword(s):  
Transient Receptor Potential ◽  
Purinergic Receptor ◽  
Critical Role ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Receptor Activation ◽  
Myogenic Tone ◽  
Pial Arteries ◽  
Myogenic Regulation

Cerebral parenchymal arterioles (PAs) have a critical role in assuring appropriate blood flow and perfusion pressure within the brain. They are unique in contrast to upstream pial arteries, as defined by their critical roles in neurovascular coupling, distinct sensitivities to chemical stimulants, and enhanced myogenic tone development. The objective of the present study was to reveal some of the unique mechanisms of myogenic tone regulation in the cerebral microcirculation. Here, we report that in vivo suppression of TRPM4 (transient receptor potential) channel expression, or inhibition of TRPM4 channels with 9-phenanthrol substantially reduced myogenic tone of isolated PAs, supporting a key role of TRPM4 channels in PA myogenic tone development. Further, downregulation of TRPM4 channels inhibited vasoconstriction induced by the specific P2Y4 and P2Y6 receptor ligands (UTP γS and UDP) by 37% and 42%, respectively. In addition, 9-phenanthrol substantially attenuated purinergic ligand-induced membrane depolarization and constriction of PAs, and inhibited ligand-evoked TRPM4 channel activation in isolated PA myocytes. In concert with our previous work showing the essential contributions of P2Y4 and P2Y6 receptors to myogenic regulation of PAs, the current results point to TRPM4 channels as an important link between mechanosensitive P2Y receptor activation and myogenic constriction of cerebral PAs.

Abstract 358: Transient Receptor Potential Vanilloid 2 (TRPV2) contributes to myocardial contractility and hypertrophy via sarcoplasmic reticulum calcium handling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jack Rubinstein ◽  
Vivek P Singh ◽  
Valerie M Lasko ◽  
Sheryl E Koch ◽  
Evangelia Kranias ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Fold Increase ◽  
Calcium Handling ◽  
Heart Weight ◽  
Transient Receptor Potential Vanilloid ◽  
Cardiomyocyte Contractility ◽  
Transient Receptor

Background: TRPV2 is a Ca2+ channel that we have recently discovered in cardiomyocytes. The absence of this channel negatively impacts baseline contractility while stimulation results in a positive inotropic response. What remains to be established is the mechanism of this receptor and its role, if any, in the development of hypertrophy. Methods and Results: We obtained isolated cardiomyocytes from wild type (WT) and TRPV2-/- (KO) mice and found that the sarcoplasmic reticulum Ca2+ content and Ca2+ transients were reduced along with fractional shortening in the KO cardiomyocytes (figure, panels A, B, C). In vivo echocardiography confirmed a decrease in ejection fraction in KO mice in comparison to the WT counterparts (panel D). The relevance of these findings was examined in 6 WT and 5 KO mice subjected to transverse aortic constriction (TAC). These mice were followed by echocardiography weekly for a total of 8 weeks post TAC. At the conclusion, the hearts were obtained for histological and molecular analyses. We demonstrated that the KO mice developed less LV hypertrophy in comparison to WT (via echocardiography and by heart weight/body weight ratios) (figure, panels E and F). Importantly, there was a 5 fold increase in TRPV2 expression assessed by PCR in TAC WT hearts, compared to WT not subjected to TAC (0.72±0.10 vs. 0.13±0.04; p<0.01). This suggests a role for TRPV2 not only in contractility, but also in the development of hypertrophy. Conclusions: We have discovered a novel cardiac channel that alters Ca2+ cycling and is capable of modulating cardiomyocyte contractility and hypertrophy, which could lead to novel therapeutic options in heart failure and hypertrophy.

scholarly journals Peripheral Mechanobiology of Touch—Studies on Vertebrate Cutaneous Sensory Corpuscles

2020 ◽  
Vol 21 (17) ◽  
pp. 6221 ◽  
Author(s):  
Ramón Cobo ◽  
Jorge García-Piqueras ◽  
Yolanda García-Mesa ◽  
Jorge Feito ◽  
Olivia García-Suárez ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Mechanical Stimulus ◽  
Nerve Fibers ◽  
Current Data ◽  
Acid Sensing Ion Channels ◽  
Low Threshold ◽  
Transient Receptor

The vertebrate skin contains sensory corpuscles that are receptors for different qualities of mechanosensitivity like light brush, touch, pressure, stretch or vibration. These specialized sensory organs are linked anatomically and functionally to mechanosensory neurons, which function as low-threshold mechanoreceptors connected to peripheral skin through Aβ nerve fibers. Furthermore, low-threshold mechanoreceptors associated with Aδ and C nerve fibers have been identified in hairy skin. The process of mechanotransduction requires the conversion of a mechanical stimulus into electrical signals (action potentials) through the activation of mechanosensible ion channels present both in the axon and the periaxonal cells of sensory corpuscles (i.e., Schwann-, endoneurial- and perineurial-related cells). Most of those putative ion channels belong to the degenerin/epithelial sodium channel (especially the family of acid-sensing ion channels), the transient receptor potential channel superfamilies, and the Piezo family. This review updates the current data about the occurrence and distribution of putative mechanosensitive ion channels in cutaneous mechanoreceptors including primary sensory neurons and sensory corpuscles.

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