Carvacrol Decreases Neuronal Excitability by Inhibition of Voltage-Gated Sodium Channels

2012 ◽  
Vol 75 (9) ◽  
pp. 1511-1517 ◽  
Author(s):  
Humberto Cavalcante Joca ◽  
Yuri Cruz-Mendes ◽  
Klausen Oliveira-Abreu ◽  
Rebeca Peres Moreno Maia-Joca ◽  
Roseli Barbosa ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Neuronal Excitability ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Fibroblast Growth Factor Homologous Factors Control Neuronal Excitability through Modulation of Voltage-Gated Sodium Channels

Neuron ◽  
2007 ◽  
Vol 55 (3) ◽  
pp. 449-463 ◽  
Author(s):  
Mitchell Goldfarb ◽  
Jon Schoorlemmer ◽  
Anthony Williams ◽  
Shyam Diwakar ◽  
Qing Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Sodium Channels ◽  
Neuronal Excitability ◽  
Fibroblast Growth ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals CK2 activity is required for the interaction of FGF14 with voltage‐gated sodium channels and neuronal excitability

2016 ◽  
Vol 30 (6) ◽  
pp. 2171-2186 ◽  
Author(s):  
Wei‐Chun J. Hsu ◽  
Federico Scala ◽  
Miroslav N. Nenov ◽  
Norelle C. Wildburger ◽  
Hannah Elferink ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Neuronal Excitability ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Non-SUMOylated CRMP2 decreases NaV1.7 currents via the endocytic proteins Numb, Nedd4-2 and Eps15

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kimberly Gomez ◽  
Dongzhi Ran ◽  
Cynthia L. Madura ◽  
Aubin Moutal ◽  
Rajesh Khanna
Keyword(s):  
Sodium Channels ◽  
Mechanical Allodynia ◽  
Neuronal Excitability ◽  
Growth Factor Receptor ◽  
Functional Expression ◽  
Voltage Gated ◽  
Female Mice ◽  
Voltage Gated Sodium Channels ◽  
Endocytic Proteins

AbstractVoltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel NaV1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). When not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of NaV1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2K374A/K374A) female mice have reduced NaV1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2K374A/K374A female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male CRMP2K374A/K374A mice precipitated mechanical allodynia in mice otherwise resistant to developing persistent pain. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2K374A/K374A mice. Finally, silencing these proteins in DRG neurons from female CRMP2K374A/K374A mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non-SUMOylated CRMP2-mediated internalization of sodium channels in vivo.

scholarly journals µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission

2017 ◽  
Author(s):  
Elisabetta Tosti ◽  
Raffaele Boni ◽  
Alessandra Gallo
Keyword(s):  
Sodium Channels ◽  
Pain Perception ◽  
Neuronal Excitability ◽  
Current Knowledge ◽  
Disulfide Bridges ◽  
Post Translational Modifications ◽  
Active Peptides ◽  
Voltage Gated ◽  
Common Structure ◽  
Voltage Gated Sodium Channels

The Conus genus includes around 500 species of marine mollusks with a peculiar production of venomous peptides known as conotoxins (CTX). Each species is able to produce up to 200 different biological active peptides. Common structure of CTX is the low number of aminoacids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µ-O CTX are two isoforms that specifically target voltage-gated sodium channels. These, by inducing the entrance of sodium ions in the cell, modulate the neuronal excitability by depolarizing plasma membrane and propagating the action potential. Hyperxcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and neuropathic pain states. In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their potential therapeutic use as analgesic compounds in the clinical management of pain conditions.

scholarly journals Studies on CRMP2 SUMOylation-deficient transgenic mice reveal novel insights into the trafficking of NaV1.7 channels

2020 ◽  
Author(s):  
Kimberly Gomez ◽  
Dongzhi Ran ◽  
Cynthia L. Madura ◽  
Aubin Moutal ◽  
Rajesh Khanna
Keyword(s):  
Sodium Channels ◽  
Neuronal Excitability ◽  
Growth Factor Receptor ◽  
Functional Expression ◽  
Male And Female ◽  
Voltage Gated ◽  
Female Mice ◽  
Voltage Gated Sodium Channels ◽  
Mediator Protein

AbstractVoltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel NaV1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). If not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of NaV1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2K374A/K374A) female mice have reduced NaV1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2K374A/K374A female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male and female CRMP2K374A/K374A mice, increased pain sensitivity in allodynia-resistant animals. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2K374A/K374A mice. Finally, silencing these proteins in DRG neurons from female CRMP2K374A/K374A mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non SUMOylated CRMP2-mediated internalization of sodium channels in vivo.

scholarly journals Ca2+-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Hao-Song Shi ◽  
Ke Lai ◽  
Xin-Lu Yin ◽  
Min Liang ◽  
Hai-Bo Ye ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Neuronal Excitability ◽  
Balance Control ◽  
Vestibular Nucleus ◽  
Neurological Deficits ◽  
Medial Vestibular Nucleus ◽  
Cellular Mechanisms ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Immunofluorescence Labeling

Abstract Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca2+ overload, and neurotoxicity. However, the cellular mechanisms underlying elevated neuronal excitability remain unknown. By performing patch-clamp recordings from neonatal neurons in the rat medial vestibular nucleus (MVN), a crucial relay station for locomotor and balance control, we found that BIL (3 μM) drastically increases the spontaneous firing rates by upregulating the current-mediated voltage-gated sodium channels (VGSCs), while shifting their voltage-dependent activation toward more hyperpolarized potentials. Immunofluorescence labeling and western immunoblotting with an anti-NaV1.1 antibody, revealed that BIL elevates the expression of VGSCs by promoting their recruitment to the membrane. Furthermore, we found that this VGSC-trafficking process is Ca2+ dependent because preloading MVN neurons with the Ca2+ buffer BAPTA-AM, or exocytosis inhibitor TAT-NSF700, prevents the effects of BIL, indicating the upregulated activity and density of functional VGSCs as the core mechanism accountable for the BIL-induced overexcitation of neonatal neurons. Most importantly, rectification of such overexcitation with a low dose of VGSC blocker lidocaine significantly attenuates BIL-induced cell death. We suggest that this enhancement of VGSC currents directly contributes to the vulnerability of neonatal brain to hyperbilirubinemia, implicating the activity and trafficking of NaV1.1 channels as a potential target for neuroprotection in cases of severe jaundice.

scholarly journals BmK AEP, an Anti-Epileptic Peptide Distinctly Affects the Gating of Brain Subtypes of Voltage-Gated Sodium Channels

2019 ◽  
Vol 20 (3) ◽  
pp. 729 ◽  
Author(s):  
Fan Zhang ◽  
Ying Wu ◽  
Xiaohan Zou ◽  
Qinglian Tang ◽  
Fang Zhao ◽  
...  
Keyword(s):  
Steady State ◽  
Sodium Channels ◽  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Epileptic Activity ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Na Currents ◽  
Ic50 Value ◽  
Steady State Inactivation

BmK AEP, a scorpion peptide purified form the venom of Buthus martensii Karsch, has been reported to display anti-epileptic activity. Voltage-gated sodium channels (VGSCs) are responsible for the rising phase of action potentials (APs) in neurons and, therefore, controlling neuronal excitability. To elucidate the potential molecular mechanisms responsible for its anti-epileptic activity, we examined the influence of BmK AEP on AP firing in cortical neurons and how BmK AEP influences brain subtypes of VGSCs (Nav1.1–1.3 and Nav1.6). BmK AEP concentration-dependently suppresses neuronal excitability (AP firing) in primary cultured cortical neurons. Consistent with its inhibitory effect on AP generation, BmK AEP inhibits Na+ peak current in cortical neurons with an IC50 value of 2.12 µM by shifting the half-maximal voltage of activation of VGSC to hyperpolarized direction by ~7.83 mV without affecting the steady-state inactivation. Similar to its action on Na+ currents in cortical neurons, BmK AEP concentration-dependently suppresses the Na+ currents of Nav1.1, Nav1.3, and Nav1.6, which were heterologously expressed in HEK-293 cells, with IC50 values of 3.20, 1.46, and 0.39 µM with maximum inhibition of 82%, 56%, and 93%, respectively. BmK AEP shifts the voltage-dependent activation in the hyperpolarized direction by ~15.60 mV, ~9.97 mV, and ~6.73 mV in Nav1.1, Nav1.3, and Nav1.6, respectively, with minimal effect on steady-state inactivation. In contrast, BmK AEP minimally suppresses Nav1.2 currents (~15%) but delays the inactivation of the channel with an IC50 value of 1.69 µM. Considered together, these data demonstrate that BmK AEP is a relatively selective Nav1.6 gating modifier which distinctly affects the gating of brain subtypes of VGSCs.

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