The Transient Receptor Potential Vanilloid 4 Agonist RN-1747 Inhibits the Calcium Response to Histamine

Pharmacology ◽  
2019 ◽  
Vol 104 (3-4) ◽  
pp. 166-172 ◽  
Author(s):  
Beatrix Pfanzagl ◽  
Roswitha Pfragner ◽  
Erika Jensen-Jarolim
Keyword(s):  
Hela Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Inhibitory Effect ◽  
Cation Channels ◽  
Transient Receptor Potential Vanilloid ◽  
Calcium Response ◽  
Intestinal Hypersensitivity ◽  
Transient Receptor ◽  
Line P

Background: Sensitization of transient receptor potential (TRP) cation channels probably contributes to intestinal hypersensitivity, a hallmark of gastrointestinal disorders. Histamine acting via histamine 1 receptor (H1R) to open TRP cation channels might also be involved. Method: The enterochromaffin cell line P-STS, responsive to histamine via H1R, was used as model to study possible synergism between histamine and TRP vanilloid 4 (TRPV4) pathways. Results: The TRPV4 antagonist RN-1734, but not HC-067047, inhibited the cytoplasmic calcium response to histamine in P-STS cells. However, also pre-incubation with the TRPV4 agonist RN-1747 strongly inhibited the calcium response to histamine in P-STS as well as HeLa cells. This inhibitory effect of RN-1747 was not due to its known TRP melastatin 8 (TRPM8) antagonism, as the TRPM8 antagonist RQ-00203078 showed no significant effect on the histamine-induced calcium response of P-STS or HeLa cells. Conclusion: The TRPV4 agonist RN-1747, and possibly also the structurally similar TRPV4 antagonist RN-1734, should be used with caution because of yet unidentified interference with histamine signaling via H1R.

scholarly journals Eugenol Inhibits Sodium Currents in Dental Afferent Neurons

2006 ◽  
Vol 85 (10) ◽  
pp. 900-904 ◽  
Author(s):  
C.-K. Park ◽  
H.Y. Li ◽  
K.-Y. Yeon ◽  
S.J. Jung ◽  
S.-Y. Choi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Inhibitory Effect ◽  
Transient Receptor Potential Vanilloid ◽  
Afferent Neurons ◽  
Patch Clamp Technique ◽  
Independent Manner ◽  
Pre Treatment ◽  
Transient Receptor

Although eugenol is widely used in dentistry, little is known about the molecular mechanisms responsible for its anesthetic properties. In addition to calcium channels, recently demonstrated by our group, there could be another molecular target for eugenol. Using a whole-cell patch-clamp technique, we investigated the effect of eugenol on voltage-gated sodium channel currents ( I Na) in rat dental primary afferent neurons identified by retrograde labeling with a fluorescent dye in maxillary molars. Eugenol inhibited action potentials and I Na in both capsaicin-sensitive and capsaicin-insensitive neurons. The pre-treatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid 1 (TRPV1), failed to block the inhibitory effect of eugenol on I Na, suggesting no involvement of TRPV1. Two types of I Na, tetrodotoxin (TTX)-resistant and TTX-sensitive I Na, were inhibited by eugenol. Our results demonstrated that eugenol inhibits I Na in a TRPV1-independent manner. We suggest that I Na inhibition by eugenol contributes to its analgesic effect.

scholarly journals A Molecular Basis for the Inhibition of Transient Receptor Potential Vanilloid Type 1 by Gomisin A

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Sung Bae Lee ◽  
Shinhwa Noh ◽  
Hye Duck Yeom ◽  
Heejin Jo ◽  
Sanung Eom ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Inhibitory Effect ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Double Mutation ◽  
Extracellular Region ◽  
Gomisin A ◽  
Transient Receptor

Transient receptor potential (TRP) channel has critical actions as conditional sensors in primary afferent neurons. We studied the regulatory action of gomisin A on TRPV1 channel current in this report. Schisandra chinensis contains bioactive compounds such as the gomisin derivatives and their related compounds. Coapplication with gomisin A inhibited the capsaicin-mediated inward peak current. This inhibitory effect of gomisin A on capsaicin-induced inward current showed concentration-dependence and was reversible. The half maximal inhibitory concentration of gomisin A was 62.7±8.4 µM. In addition, this inhibition occurred in a noncompetition regulation mode and voltage insensitive manner. Furthermore, molecular docking studies of gomisin A on TRPV1 showed that it interacted predominantly with residues at cavities in the segments 1 and 2 of each subunit. Four potential binding sites for this ligand in the extracellular region at sensor domain of TRPV1 channel were identified. Point mutagenesis studies were undertaken, and gomisin A potency decreased for both the Y453A and N467A mutants. The double mutation of Y453 and N467 significantly attenuated inhibitory effects by gomisin A. In summary, this study revealed the molecular basis for the interaction between TRPV1 and gomisin A and provides a novel potent interaction ligand.

scholarly journals Coexpression and activation of TRPV1 suppress the activity of the KCNQ2/3 channel

2011 ◽  
Vol 138 (3) ◽  
pp. 341-352 ◽  
Author(s):  
Xu-Feng Zhang ◽  
Ping Han ◽  
Torben R. Neelands ◽  
Steve McGaraughty ◽  
Prisca Honore ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Receptor Potential ◽  
Inhibitory Effect ◽  
Negative Regulator ◽  
Hek293 Cells ◽  
Transient Receptor Potential Vanilloid ◽  
Hek 293 ◽  
Dorsal Root Ganglia Neurons ◽  
Transient Receptor

Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel expressed predominantly in peripheral nociceptors. By detecting and integrating diverse noxious thermal and chemical stimuli, and as a result of its sensitization by inflammatory mediators, the TRPV1 receptor plays a key role in inflammation-induced pain. Activation of TRPV1 leads to a cascade of pro-nociceptive mechanisms, many of which still remain to be identified. Here, we report a novel effect of TRPV1 on the activity of the potassium channel KCNQ2/3, a negative regulator of neuronal excitability. Using ion influx assays, we revealed that TRPV1 activation can abolish KCNQ2/3 activity, but not vice versa, in human embryonic kidney (HEK)293 cells. Electrophysiological studies showed that coexpression of TRPV1 caused a 7.5-mV depolarizing shift in the voltage dependence of KCNQ2/3 activation compared with control expressing KCNQ2/3 alone. Furthermore, activation of TRPV1 by capsaicin led to a 54% reduction of KCNQ2/3-mediated current amplitude and attenuation of KCNQ2/3 activation. The inhibitory effect of TRPV1 appears to depend on Ca2+ influx through the activated channel followed by Ca2+-sensitive depletion of phosphatidylinositol 4,5-bisphosphate and activation of protein phosphatase calcineurin. We also identified physical interactions between TRPV1 and KCNQ2/3 coexpressed in HEK293 cells and in rat dorsal root ganglia neurons. Mutation studies established that this interaction is mediated predominantly by the membrane-spanning regions of the respective proteins and correlates with the shift of KCNQ2/3 activation. Collectively, these data reveal that TRPV1 activation may deprive neurons from inhibitory control mediated by KCNQ2/3. Such neurons may thus have a lower threshold for activation, which may indirectly facilitate TRPV1 in integrating multiple noxious signals and/or in the establishment or maintenance of chronic pain.

scholarly journals TRPing to the Point of Clarity: Understanding the Function of the Complex TRPV4 Ion Channel

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 165
Author(s):  
Trine L. Toft-Bertelsen ◽  
Nanna MacAulay
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Structural Features ◽  
Cation Channels ◽  
Transient Receptor Potential Vanilloid ◽  
Post Translational Modifications ◽  
Disease States ◽  
Health And Disease ◽  
Transient Receptor

The transient receptor potential vanilloid 4 channel (TRPV4) belongs to the mammalian TRP superfamily of cation channels. TRPV4 is ubiquitously expressed, activated by a disparate array of stimuli, interacts with a multitude of proteins, and is modulated by a range of post-translational modifications, the majority of which we are only just beginning to understand. Not surprisingly, a great number of physiological roles have emerged for TRPV4, as have various disease states that are attributable to the absence, or abnormal functioning, of this ion channel. This review will highlight structural features of TRPV4, endogenous and exogenous activators of the channel, and discuss the reported roles of TRPV4 in health and disease.

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