scholarly journals Phosphoinositides regulate the TRPV1 channel via two functionally distinct binding sites

2019 ◽  
Author(s):  
Aysenur Torun Yazici ◽  
Eleonora Gianti ◽  
Marina A. Kasimova ◽  
Vincenzo Carnevale ◽  
Tibor Rohacs
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Distinct Site ◽  
Excised Patches ◽  
Transient Receptor ◽  
Dynamics Simulations

AbstractRegulation of the heat- and capsaicin-activated Transient Receptor Potential Vanilloid 1 (TRPV1) channel by phosphoinositides is controversial. In a recent cryoEM structure, an endogenous phosphoinositide was detected in the vanilloid binding site, and phosphoinositides were proposed to act as competitive vanilloid antagonists. This model is difficult to reconcile with phosphatidylinositol 4,5- bisphosphate [PtdIns(4,5)P2] being a well established positive regulator of TRPV1. To resolve this controversy, we propose that phosphoinositides regulate TRPV1 via two functionally distinct binding sites. Our molecular dynamics simulations show that phosphatidylinositol (PtdIns) is more stable in the vanilloid binding site, whereas a distinct site responsible for activation is preferentially occupied by PtdIns(4,5)P2. Consistently, we show that in the presence of PtdIns(4,5)P2 in excised patches PtdIns partially inhibited TRPV1 activity induced by low, but not high capsaicin concentrations. In the absence of PtdIns(4,5)P2 on the other hand, PtdIns partially stimulated TRPV1 activity presumably by binding to the activating site. Overall, our data resolve a major controversy in the regulation of TRPV1.

scholarly journals TRPV1: Structure, Endogenous Agonists, and Mechanisms

2020 ◽  
Vol 21 (10) ◽  
pp. 3421 ◽  
Author(s):  
Miguel Benítez-Angeles ◽  
Sara Luz Morales-Lázaro ◽  
Emmanuel Juárez-González ◽  
Tamara Rosenbaum
Keyword(s):  
Ion Channel ◽  
Binding Sites ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Field Of Study ◽  
Transient Receptor ◽  
Shed Light ◽  
Made In

The Transient Receptor Potential Vanilloid 1 (TRPV1) channel is a polymodal protein with functions widely linked to the generation of pain. Several agonists of exogenous and endogenous nature have been described for this ion channel. Nonetheless, detailed mechanisms and description of binding sites have been resolved only for a few endogenous agonists. This review focuses on summarizing discoveries made in this particular field of study and highlighting the fact that studying the molecular details of activation of the channel by different agonists can shed light on biophysical traits that had not been previously demonstrated.

scholarly journals Pore Helix Domain Is Critical to Camphor Sensitivity of Transient Receptor Potential Vanilloid 1 Channel

2012 ◽  
Vol 116 (4) ◽  
pp. 903-917 ◽  
Author(s):  
Lenka Marsakova ◽  
Filip Touska ◽  
Jan Krusek ◽  
Viktorie Vlachova
Keyword(s):  
Spatial Distribution ◽  
Plasma Membranes ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Structural Basis ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Patch Clamp Technique ◽  
Trpv1 Channels ◽  
Transient Receptor

Background The recent discovery that camphor activates and strongly desensitizes the capsaicin-sensitive and noxious heat-sensitive channel transient receptor potential vanilloid subfamily member 1 (TRPV1) has provided new insights and opened up new research paths toward understanding why this naturally occurring monoterpene is widely used in human medicine for its local counter-irritant, antipruritic, and anesthetic properties. However, the molecular basis for camphor sensitivity remains mostly unknown. The authors attempt to explore the nature of the activation pathways evoked by camphor and narrow down a putative interaction site at TRPV1. Methods The authors transiently expressed wild-type or specifically mutated recombinant TRPV1 channels in human embryonic kidney cells HEK293T and recorded cation currents with the whole cell, patch clamp technique. To monitor changes in the spatial distribution of phosphatidylinositol 4,5-bisphosphate, they used fluorescence resonance energy transfer measurements from cells transfected with the fluorescent protein-tagged pleckstrin homology domains of phospholipase C. Results The results revealed that camphor modulates TRPV1 channel through the outer pore helix domain by affecting its overall gating equilibrium. In addition, camphor, which generally is known to decrease the fluidity of cell plasma membranes, may also regulate the activity of TRPV1 by inducing changes in the spatial distribution of phosphatidylinositol-4,5-bisphosphate on the inner leaflet of the plasma membrane. Conclusions The findings of this study provide novel insights into the structural basis for the modulation of TRPV1 channel by camphor and may provide an explanation for the mechanism by which camphor modulates thermal sensation in vivo.

scholarly journals β-Arrestin-2 Desensitizes the Transient Receptor Potential Vanilloid 1 (TRPV1) Channel

2012 ◽  
Vol 287 (44) ◽  
pp. 37552-37563 ◽  
Author(s):  
Elaine D. Por ◽  
Sonya M. Bierbower ◽  
Kelly A. Berg ◽  
Ruben Gomez ◽  
Armen N. Akopian ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Transient Receptor

scholarly journals Electroacupuncture Reduces Cold Stress-Induced Pain through Microglial Inactivation and Transient Receptor Potential V1 in Mice

2021 ◽  
Author(s):  
Hsien-Yin Liao ◽  
Yi-Wen Lin
Keyword(s):  
Cold Stress ◽  
Inflammatory Mediators ◽  
Treatment Efficacy ◽  
Sensory Input ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Thermal Pain ◽  
Transient Receptor

Abstract Background Fibromyalgia pain lacks objective parameters to measure treatment efficacy. Fibromyalgia patients suffer from chronic and persistent widespread pain and generalized tenderness. Transient receptor potential V1 (TRPV1), which is reported as a Ca2+ permeable ion channel that can be activated by inflammation, is reported to be involved in the development of fibromyalgia pain. Methods The current study explored the transient receptor potential vanilloid 1 (TRPV1) channel functions as a noxious sensory input in mice cold stress model. It remains unknown whether electroacupuncture (EA) attenuates fibromyalgia pain or affects the TRPV1 pathway. Results We show that cold stress increases mechanical and thermal pain (Day 7: mechanical: 1.69 ± 0.41 g; thermal: 4.68 ± 0.56 s), and that EA and Trpv1 deletion counter this increase. EA and Trpv1 deletion reduced the cold stress-induced increase in inflammatory mediators and TRPV1-related molecules in the hypothalamus, periaqueductal gray (PAG), and cerebellum of mice. Conclusions Our results imply that EA has an analgesic effect associated with TRPV1 downregulation. We provide novel evidence that these inflammatory mediators can modulate the TRPV1 signaling pathway and suggest new potential therapeutic targets for fibromyalgia pain.

scholarly journals Contribution of the TRPV1 channel to salt taste quality in mice as assessed by conditioned taste aversion generalization and chorda tympani nerve responses

2012 ◽  
Vol 303 (11) ◽  
pp. R1195-R1205 ◽  
Author(s):  
Kimberly R. Smith ◽  
Yada Treesukosol ◽  
A. Brennan Paedae ◽  
Robert J. Contreras ◽  
Alan C. Spector
Keyword(s):  
Citric Acid ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Taste Quality ◽  
Transient Receptor Potential Vanilloid ◽  
Chorda Tympani ◽  
Chorda Tympani Nerve ◽  
Trpv1 Channel ◽  
Salt Taste ◽  
Transient Receptor

In rodents, at least two transduction mechanisms are involved in salt taste: 1) the sodium-selective epithelial sodium channel, blocked by topical amiloride administration, and 2) one or more amiloride-insensitive cation-nonselective pathways. Whereas electrophysiological evidence from the chorda tympani nerve (CT) has implicated the transient receptor potential vanilloid-1 (TRPV1) channel as a major component of amiloride-insensitive salt taste transduction, behavioral results have provided only equivocal support. Using a brief-access taste test, we examined generalization profiles of water-deprived C57BL/6J (WT) and TRPV1 knockout (KO) mice conditioned (via LiCl injection) to avoid 100 μM amiloride-prepared 0.25 M NaCl and tested with 0.25 M NaCl, sodium gluconate, KCl, NH4Cl, 6.625 mM citric acid, 0.15 mM quinine, and 0.5 M sucrose. Both LiCl-injected WT and TRPV1 KO groups learned to avoid NaCl+amiloride relative to controls, but their generalization profiles did not differ; LiCl-injected mice avoided the nonsodium salts and quinine suggesting that a TRPV1-independent pathway contributes to the taste quality of the amiloride-insensitive portion of the NaCl signal. Repeating the experiment but doubling all stimulus concentrations revealed a difference in generalization profiles between genotypes. While both LiCl-injected groups avoided the nonsodium salts and quinine, only WT mice avoided the sodium salts and citric acid. CT responses to these stimuli and a concentration series of NaCl and KCl with and without amiloride did not differ between genotypes. Thus, in our study, TRPV1 did not appear to contribute to sodium salt perception based on gustatory signals, at least in the CT, but may have contributed to the oral somatosensory features of sodium.

scholarly journals Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation

2020 ◽  
Author(s):  
Mathieu Botte ◽  
Alexander K. C. Ulrich ◽  
Ricardo Adaixo ◽  
David Gnutt ◽  
Andreas Brockmann ◽  
...  
Keyword(s):  
Ion Channel ◽  
Binding Site ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Structural Information ◽  
Critical Role ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Open Conformation ◽  
Transient Receptor

ABSTRACTThe human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4.

Functional Mapping of the Transient Receptor Potential Vanilloid 1 Intracellular Binding Site

2006 ◽  
Vol 70 (3) ◽  
pp. 1005-1012 ◽  
Author(s):  
Daniel M. Johnson ◽  
Elizabeth M. Garrett ◽  
Richard Rutter ◽  
Timothy P. Bonnert ◽  
Ying-Duo Gao ◽  
...  
Keyword(s):  
Binding Site ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Functional Mapping ◽  
Transient Receptor Potential Vanilloid ◽  
Intracellular Binding ◽  
Transient Receptor

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.

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