Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

2014 ◽  
Vol 53 (1) ◽  
pp. 759-768 ◽  
Author(s):  
Zhiwen Hong ◽  
Pinghui Jie ◽  
Yujing Tian ◽  
Tingting Chen ◽  
Lei Chen ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Hippocampal Neurons ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Transient Receptor

scholarly journals Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation

2021 ◽  
Vol 55 (S3) ◽  
pp. 108-130
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Transmembrane Helices ◽  
Endogenous Ligands ◽  
Voltage Gated ◽  
Kv Channels ◽  
Trpv Channels ◽  
Transient Receptor ◽  
Pain Stimuli

Transient receptor potential vanilloid (TRPV) channels are part of the TRP channel superfamily and named after the first identified member TRPV1, that is sensitive to the vanillylamide capsaicin. Their overall structure is similar to the structure of voltage gated potassium channels (Kv) built up as homotetramers from subunits with six transmembrane helices (S1-S6). Six TRPV channel subtypes (TRPV1-6) are known, that can be subdivided into the thermoTRPV (TRPV1-4) and the Ca2+-selective TRPV channels (TRPV5, TRPV6). Contrary to Kv channels, TRPV channels are not primary voltage gated. All six channels have distinct properties and react to several endogenous ligands as well as different gating stimuli such as heat, pH, mechanical stress, or osmotic changes. Their physiological functions are highly diverse and subtype as well as tissue specific. In many tissues they serve as sensors for different pain stimuli (heat, pressure, pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions and the development of macrophages. Due to their fundamental role in manifold physiological and pathophysiological processes, TRPV channels are promising targets for drug development. However, drugs targeting specific TRPV channels, that are suitable for drug therapy, are rare. Moreover, selective and potent compounds for further research at TRPV channels are often lacking. In this review different aspects of the structure, the different gating stimuli, the expression pattern, the physiological and pathophysiological roles as well as the modulating mechanisms of synthetic, natural and endogenous ligands are summarized.

scholarly journals TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress

2021 ◽  
Vol 14 ◽  
Author(s):  
Michael L. Risner ◽  
Nolan R. McGrady ◽  
Andrew M. Boal ◽  
Silvia Pasini ◽  
David J. Calkins
Keyword(s):  
Transient Receptor Potential ◽  
Ganglion Cells ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Membrane Excitability ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Early Progression ◽  
Dendritic Organization ◽  
Dendritic Complexity

Early progression in neurodegenerative disease involves challenges to homeostatic processes, including those controlling axonal excitability and dendritic organization. In glaucoma, the leading cause of irreversible blindness, stress from intraocular pressure (IOP) causes degeneration of retinal ganglion cells (RGC) and their axons which comprise the optic nerve. Previously, we discovered that early progression induces axogenic, voltage-gated enhanced excitability of RGCs, even as dendritic complexity in the retina reduces. Here, we investigate a possible contribution of the transient receptor potential vanilloid type 1 (TRPV1) channel to enhanced excitability, given its role in modulating excitation in other neural systems. We find that genetic deletion of Trpv1 (Trpv1−/−) influences excitability differently for RGCs firing continuously to light onset (αON-Sustained) vs. light offset (αOFF-Sustained). Deletion drives excitability in opposing directions so that Trpv1−/− RGC responses with elevated IOP equalize to that of wild-type (WT) RGCs without elevated IOP. Depolarizing current injections in the absence of light-driven presynaptic excitation to directly modulate voltage-gated channels mirrored these changes, while inhibiting voltage-gated sodium channels and isolating retinal excitatory postsynaptic currents abolished both the differences in light-driven activity between WT and Trpv1−/− RGCs and changes in response due to IOP elevation. Together, these results support a voltage-dependent, axogenic influence of Trpv1−/− with elevated IOP. Finally, Trpv1−/− slowed the loss of dendritic complexity with elevated IOP, opposite its effect on axon degeneration, supporting the idea that axonal and dendritic degeneration follows distinctive programs even at the level of membrane excitability.

scholarly journals Eugenol Inhibits K+ Currents in Trigeminal Ganglion Neurons

2007 ◽  
Vol 86 (9) ◽  
pp. 898-902 ◽  
Author(s):  
H.Y. Li ◽  
C.-K. Park ◽  
S.J. Jung ◽  
S.-Y. Choi ◽  
S.J. Lee ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Inhibitory Effects ◽  
Independent Manner ◽  
Voltage Gated ◽  
Trigeminal Ganglion Neurons ◽  
Transient Receptor ◽  
Ganglion Neurons

Eugenol, a natural capsaicin congener, is widely used in dentistry. Eugenol inhibits voltage-activated Na+ and Ca2+ channels in a transient receptor potential vanilloid 1 (TRPV1)-independent manner. We hypothesized that eugenol also inhibits voltage-gated K+ currents, and investigated this in rat trigeminal ganglion neurons and in a heterologous system using whole-cell patch clamping. Eugenol inhibited voltage-gated K+ currents, and the inhibitory effects of eugenol were observed in both capsaicin-sensitive and capsaicin-insensitive neurons. Pre-treatment with capsazepine, a well-known antagonist of TRPV1, failed to block the inhibitory effects of eugenol on K+ currents, suggesting no involvement of TRPV1. Eugenol inhibited human Kv1.5 currents stably expressed in Ltk− cells, where TRPV1 is not endogenously expressed. We conclude that eugenol inhibits voltage-gated K+ currents in a TRPV1-independent manner. The inhibition of voltage-gated K+ currents is likely to contribute to the irritable action of eugenol. Abbreviations: human Kv1.5 channel, hKv1.5; transient receptor potential vanilloid 1, TRPV1.

scholarly journals Receptors and Channels Possibly Mediating the Effects of Phytocannabinoids on Seizures and Epilepsy

2020 ◽  
Vol 13 (8) ◽  
pp. 174 ◽  
Author(s):  
Lara Senn ◽  
Giuseppe Cannazza ◽  
Giuseppe Biagini
Keyword(s):  
Transient Receptor Potential ◽  
Cannabinoid Receptor ◽  
Receptor Potential ◽  
Epileptic Seizures ◽  
Transient Receptor Potential Vanilloid ◽  
Clinical Value ◽  
Positive Effects ◽  
Voltage Gated Sodium Channels ◽  
Transient Receptor ◽  
Sites Of Action

Epilepsy contributes to approximately 1% of the global disease burden. By affecting especially young children as well as older persons of all social and racial variety, epilepsy is a present disorder worldwide. Currently, only 65% of epileptic patients can be successfully treated with antiepileptic drugs. For this reason, alternative medicine receives more attention. Cannabis has been cultivated for over 6000 years to treat pain and insomnia and used since the 19th century to suppress epileptic seizures. The two best described phytocannabinoids, (−)-trans-Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are claimed to have positive effects on different neurological as well as neurodegenerative diseases, including epilepsy. There are different cannabinoids which act through different types of receptors and channels, including the cannabinoid receptor 1 and 2 (CB1, CB2), G protein-coupled receptor 55 (GPR55) and 18 (GPR18), opioid receptor µ and δ, transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), type A γ-aminobutyric acid receptor (GABAAR) and voltage-gated sodium channels (VGSC). The mechanisms and importance of the interaction between phytocannabinoids and their different sites of action regarding epileptic seizures and their clinical value are described in this review.

scholarly journals Co-Application of Eugenol and QX-314 Elicits the Prolonged Blockade of Voltage-Gated Sodium Channels in Nociceptive Trigeminal Ganglion Neurons

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1513
Author(s):  
Sung-Min Hwang ◽  
Kihwan Lee ◽  
Sang-Taek Im ◽  
Eun Jin Go ◽  
Yong Ho Kim ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Trigeminal Ganglion ◽  
Transient Receptor Potential ◽  
Pain Treatment ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Noxious Heat ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Ganglion Neurons

Local anesthetics (LAs) can completely block nociception by inhibiting voltage-gated sodium channels (VGSCs), and thus, blocking action potentials (APs) within sensory neurons. As one of the several LAs, eugenol is used for dental pain treatment. It reportedly features multiple functions in regulating diverse ion channels. This study aimed to investigate the long-lasting analgesic effect of eugenol alone, as well as that of the combination of eugenol as a noxious-heat-sensitive transient receptor potential vanilloid 1 (TRPV1) channel agonist and a permanently charged sodium channel blocker (QX-314), on neuronal excitability in trigeminal ganglion (TG) neurons. Eugenol alone increased inward current in a dose-dependent manner in capsaicin-sensitive TG neurons. Eugenol also inhibited the VGSC current and AP. These effects were reversed through wash-out. The combination of eugenol and QX-314 was evaluated in the same manner. The combination completely inhibited the VGSC current and AP. However, these effects were not reversed and were continuously blocked even after wash-out. Taken together, our results suggest that, in contrast to the effect of eugenol alone, the combination of eugenol and QX-314 irreversibly and selectively blocked VGSCs in TG neurons expressing TRPV1.

Quaternary Lidocaine Derivative QX-314 Activates and Permeates Human TRPV1 and TRPA1 to Produce Inhibition of Sodium Channels and Cytotoxicity

2016 ◽  
Vol 124 (5) ◽  
pp. 1153-1165 ◽  
Author(s):  
Thomas Stueber ◽  
Mirjam J. Eberhardt ◽  
Christoph Hadamitzky ◽  
Annette Jangra ◽  
Stefan Schenk ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
Transient Receptor Potential ◽  
Sodium Current ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Viable Cells ◽  
Channel Inhibition ◽  
Transient Receptor ◽  
Human Isoforms

Abstract Background The relatively membrane-impermeable lidocaine derivative QX-314 has been reported to permeate the ion channels transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1) to induce a selective inhibition of sensory neurons. This approach is effective in rodents, but it also seems to be associated with neurotoxicity. The authors examined whether the human isoforms of TRPV1 and TRPA1 allow intracellular entry of QX-314 to mediate sodium channel inhibition and cytotoxicity. Methods Human embryonic kidney 293 (HEK-293) cells expressing wild-type or mutant human (h) TRPV1 or TRPA1 constructs as well as the sodium channel Nav1.7 were investigated by means of patch clamp and ratiometric calcium imaging. Cytotoxicity was examined by flow cytometry. Results Activation of hTRPA1 by carvacrol and hTRPV1 by capsaicin produced a QX-314–independent reduction of sodium current amplitudes. However, permeation of QX-314 through hTRPV1 or hTRPA1 was evident by a concentration-dependent, use-dependent inhibition of Nav1.7 activated at 10 Hz. Five and 30 mM QX-314 activated hTRPV1 via mechanisms involving the intracellular vanilloid-binding domain and hTRPA1 via unknown mechanisms independent of intracellular cysteins. Expression of hTRPV1, but not hTRPA1, was associated with a QX-314–induced cytotoxicity (viable cells 48 ± 5% after 30 mM QX-314) that was ameliorated by the TRPV1 antagonist 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide (viable cells 81 ± 5%). Conclusions The study data demonstrate that QX-314 directly activates and permeates the human isoforms of TRPV1 and TRPA1 to induce inhibition of sodium channels, but also a TRPV1-dependent cytotoxicity. These results warrant further validation of this approach in more intact preparations and may be valuable for the development of this concept into clinical practice.

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