Elucidation of the Role of Transient Receptor Potential Vanilloid-1 (TRPV1) Channels in Epileptogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Omar M.E. Abdel-Salam
Keyword(s):  
Transient Receptor Potential ◽  
Glutamate Release ◽  
Epileptiform Activity ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Trpv1 Receptors ◽  
Transient Receptor

The transient receptor potential vanilloid-1 (TRPV1), previously known as the capsaicin receptor or vanilloid receptor 1 (VR1) is a nonselective cation channel that acts as an integrator of nociceptive information in sensory neurons and their sensory nerve endings with unmyelinated (C) or thin myelinated (Aδ) fibers. It is activated by capsaicin, resiniferatoxin, piperine, noxious heat (> 43ºC), protons, lipoxygenase products, and some endogenous cannabinoids. TRPV1 receptors are also expressed in the brain on neurons, glia cells and pericytes and might be involved in the modulation of epileptogenesis. TRPV1 modulates synaptic plasticity and neurotransmission, mediates long-term depression of glutamate release in the hippocampus and suppress excitatory transmission in dentate gyrus. TRPV1-knockout mice have altered susceptibility to hyperthermic seizures. Studies in vitro showed that capsaicin reduced epileptiform activity but increased neuronal discharge in excitable cells. Capsaicin given via systemic routes at low doses was shown to reduce seizures induced by kainic acid and pentylenetetrazole and to afford neuroprotection of hippocampus in vivo. These effects were associated with reduced oxidative stress and inflammation in brain. In contrast, high doses of capsaicin either elicited or enhanced seizures in animals. In addition, piperine, a TRPV1 agonist, demonstrated anti-epileptic activity in several animal models via a multiplicity of mechanisms. Moreover, non-psychotropic cannabinoids such as cannabidiol and cannabidivarin, the endocannabinoid anandamide, and acetaminophen demonstrated anti-epileptiform activity in vivo and in vitro via mechanisms that might involve TRPV1 receptors. By surveying recent research findings, this review article is intended to present the current research status on the involvement of TRPV1 receptors in epileptogenesis so as to stimulate further investigations into the detailed molecular mechanisms by which capsaicin as well as other chemical modalities impact epileptogenesis via modulating TRPV1 channels. (First online: Apr 12, 2021)

scholarly journals The Quaternary Lidocaine Derivative, QX-314, Exerts Biphasic Effects on Transient Receptor Potential Vanilloid Subtype 1 Channels In Vitro 

2011 ◽  
Vol 114 (6) ◽  
pp. 1425-1434 ◽  
Author(s):  
Ricardo E. Rivera-Acevedo ◽  
Stephan A. Pless ◽  
Christopher A. Ahern ◽  
Stephan K. W. Schwarz
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Xenopus Laevis Oocytes ◽  
Sensory Blockade ◽  
Nociceptive Neurons ◽  
Trpv1 Channels ◽  
Transient Receptor

Background Transient receptor potential vanilloid subfamily member 1 (TRPV1) channels are important integrators of noxious stimuli with pronounced expression in nociceptive neurons. The experimental local anesthetic, QX-314, a quaternary (i.e., permanently charged) lidocaine derivative, recently has been shown to interact with and permeate these channels to produce nociceptive and sensory blockade in animals in vivo. However, little is known about the specific interactions between QX-314 and TRPV1 channels. Thus, the authors examined the mechanistic basis by which QX-314 acts on TRPV1 channels. Methods The authors conducted an in vitro laboratory study in which they expressed TRPV1 and TRPV4 channels in Xenopus laevis oocytes and recorded cation currents with the two-electrode voltage clamp method. They used confocal microscopy for Ca²⁺ imaging in TRPV1 transient transfected tsA201 cells. Drugs were bath-applied by gravity perfusion. Statistical analyses were performed using Student t test, ANOVA, and post tests as appropriate (P < 0.05). Results QX-314 activated TRPV1 channels at 10, 30, and 60 mM (0.4 ± 0.1%, 3.5 ± 1.3%, and 21.5 ± 6.9% of normalized peak activation, respectively; mean ± SEM; n = 12) but not TRPV4 channels (P < 0.001). Activation by QX-314 was blocked by the TRPV1 antagonist, capsazepine (100 μM). QX-314 (60 mM) activation and blockade by capsazepine was also demonstrated in Ca²⁺ imaging studies on TRPV1-expressing tsA201 cells. At subactivating concentrations (less than 1 mM), QX-314 potently inhibited capsaicin-evoked TRPV1 currents with an IC₅₀ of 8.0 ± 0.6 μM. Conclusions The results of this study show that the quaternary lidocaine derivative QX-314 exerts biphasic effects on TRPV1 channels, inhibiting capsaicin-evoked TRPV1 currents at lower (micromolar) concentrations and activating TRPV1 channels at higher (millimolar) concentrations. These findings provide novel insights into the interactions between QX-314 and TRPV1 and may provide an explanation for the irritant properties of intrathecal QX-314 in mice in vivo.

scholarly journals Hypernatremia-induced vasopressin secretion is not altered in TRPV1−/− rats

2016 ◽  
Vol 311 (3) ◽  
pp. R451-R456 ◽  
Author(s):  
Andrew Blake Tucker ◽  
Sean D. Stocker
Keyword(s):  
Intravenous Injection ◽  
Transient Receptor Potential ◽  
Plasma Osmolality ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Vasopressin Secretion ◽  
Transient Receptor

Changes in osmolality or extracellular NaCl concentrations are detected by specialized neurons in the hypothalamus to increase vasopressin (VP) and stimulate thirst. Recent in vitro evidence suggests this process is mediated by an NH2-terminal variant of the transient receptor potential vanilloid type 1 (TRPV1) channel expressed by osmosensitive neurons of the lamina terminalis and vasopressinergic neurons of the supraoptic nucleus. The present study tested this hypothesis in vivo by analysis of plasma VP levels during acute hypernatremia in awake control and TRPV1−/− rats. TRPV1−/− rats were produced by a Zinc-finger-nuclease 2-bp deletion in exon 13. Intravenous injection of the TRPV1 agonist capsaicin produced hypotension and bradycardia in control rats, but this response was absent in TRPV1−/− rats. Infusion of 2 M NaCl (1 ml/h iv) increased plasma osmolality, electrolytes, and VP levels in both control and TRPV1−/− rats. However, plasma VP levels did not differ between strains at any time. Furthermore, a linear regression between plasma VP versus osmolality revealed a significant correlation in both control and TRPV1−/− rats, but the slope of the regression lines was not attenuated in TRPV1−/− versus control rats. Hypotension produced by intravenous injection of minoxidil decreased blood pressure and increased plasma VP levels similarly in both groups. Finally, both treatments stimulated thirst; however, cumulative water intakes in response to hypernatremia or hypotension were not different between control and TRPV1−/− rats. These findings suggest that TRPV1 channels are not necessary for VP secretion and thirst stimulated by hypernatremia.

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 TRPV1 Antagonist Prevents Neonatal Sevoflurane-Induced Synaptic Abnormality and Cognitive Impairment in Mice Through Regulating the Src/Cofilin Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuqiang Liu ◽  
Han Yang ◽  
Yifei Fu ◽  
Zhenglong Pan ◽  
Fang Qiu ◽  
...  
Keyword(s):  
Cognitive Dysfunction ◽  
Hippocampal Neurons ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Newborn Mice ◽  
Trpv1 Channels ◽  
Trpv1 Antagonist

Long-term neurodevelopmental disorders following neonatal anesthesia have been reported both in young animals and in children. The activation of transient receptor potential vanilloid 1 (TRPV1) channels in hippocampus adversely affects neurodevelopment. The current study explored the underlying mechanism of TRPV1 channels on long-lasting cognitive dysfunction induced by anesthetic exposure to the developing brain. we demonstrated that TRPV1 expression was increased after sevoflurane exposure both in vitro and in vivo. Sevoflurane exposure to hippocampal neurons decreased the synaptic density and the surface GluA1 expression, as well as increased co-localization of internalized AMPAR in early and recycling endosomes. Sevoflurane exposure to newborn mice impaired learning and memory in adulthood, and reduced AMPAR subunit GluA1, 2 and 3 expressions in the crude synaptosomal fractions from mouse hippocampus. The inhibition of TRPV1 reversed the phenotypic changes induced by sevoflurane. Moreover, sevoflurane exposure increased Src phosphorylation at tyrosine 416 site thereby reducing cofilin phosphorylation. TRPV1 blockade reversed these suppressive effects of sevoflurane. Our data suggested that TRPV1 antagonist may protect against synaptic damage and cognitive dysfunction induced by sevoflurane exposure during the brain developing stage.

scholarly journals Accumulation of intramyocyte TRPV1-mediated calcium during heat stress is inhibited by concomitant muscle contractions

2019 ◽  
Vol 126 (3) ◽  
pp. 691-698 ◽  
Author(s):  
Ryo Ikegami ◽  
Hiroaki Eshima ◽  
Takuro Mashio ◽  
Tomosada Ishiguro ◽  
Daisuke Hoshino ◽  
...  
Keyword(s):  
Heat Stress ◽  
Muscle Contraction ◽  
Isometric Contraction ◽  
Calcium Concentration ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Transient Receptor

Heat stress promotes intramyocyte calcium concentration ([Ca2+]i) accumulation via transient receptor potential vanilloid 1 (TRPV1) channels. We tested the hypothesis that muscle contractile activity concomitant with heat stress would accelerate the increase in [Ca2+]i via TRPV1, further impairing [Ca2+]i homeostasis. Spinotrapezius muscles of adult Wistar rats were exteriorized in vivo and loaded with the fluorescent Ca2+ probe fura 2-AM. Heat stress (muscle surface temperature 40°C) was used as TRPV1 activator. An isometric contraction (100 Hz, 5–10 V, 30 s) was induced electrically concomitant with heat stress. [Ca2+]i was determined for 20 min using in vivo fluorescence microscopy, and the phosphorylation response of TRPV1 was determined by Western blotting. Heat stress induced a significant [Ca2+]i increase of 18.5 ± 8.1% at 20 min and TRPV1 phosphorylation (+231%), which was inhibited by addition of the TRPV1 inhibitor (capsazepine). However, contrary to expectations, the heat stress and isometric contraction condition almost completely inhibited TRPV1 phosphorylation and the consequent [Ca2+]i elevation (<2.8% accumulation during heat stress, P > 0.05). In conclusion, this in vivo physiological model demonstrated that isometric muscle contraction(s) can suppress the phosphorylation response of TRPV1 and maintain [Ca2+]i homeostasis during heat stress. NEW & NOTEWORTHY This investigation is the first document the dynamics of intramyocyte calcium concentration ([Ca2+]i) increase in the myoplasm of skeletal muscle fibers in response to heat stress where the muscle blood flow is preserved. Heat stress at 40°C drives a myoplasmic [Ca2+]i accumulation in concert with transient receptor potential vanilloid 1 (TRPV1) phosphorylation. However, muscle contraction caused TRPV1 channel deactivation by dephosphorylation of TRPV1. TRPV1 inactivation via isometric contraction(s) permits maintenance of [Ca2+]i homeostasis even under high imposed muscle temperature.

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