Control of neuronal excitability by phosphorylation and dephosphorylation of sodium channels

2006 ◽  
Vol 34 (6) ◽  
pp. 1299-1302 ◽  
Author(s):  
T. Scheuer ◽  
W.A. Catterall
Keyword(s):  
Protein Kinases ◽  
Sodium Channels ◽  
Neuronal Excitability ◽  
Sodium Current ◽  
Molecular Complexes ◽  
Neuronal Firing ◽  
Signal Integration ◽  
Excitable Cells ◽  
Signalling Molecules ◽  
Voltage Gated Sodium Channels

Currents through voltage-gated sodium channels drive action potential depolarization in neurons and other excitable cells. Smaller currents through these channels are key components of currents that control neuronal firing and signal integration. Changes in sodium current have profound effects on neuronal firing. Sodium channels are controlled by neuromodulators acting through phosphorylation of the channel by serine/threonine and tyrosine protein kinases. That phosphorylation requires specific molecular interaction of kinases and phosphatases with the channel molecule to form localized signalling complexes. Such localization is required for effective neurotransmitter-mediated regulation of sodium channels by protein kinase A. Analogous molecular complexes between sodium channels, kinases and other signalling molecules are expected to be necessary for specific and localized transmitter-mediated modulation of sodium channels by other protein kinases.

scholarly journals Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1595
Author(s):  
Agnes Zybura ◽  
Andy Hudmon ◽  
Theodore R. Cummins
Keyword(s):  
Sodium Channels ◽  
Protein Interactions ◽  
Neuronal Excitability ◽  
Neuronal Firing ◽  
Protein Protein Interactions ◽  
Membrane Excitability ◽  
Voltage Gated Sodium Channels ◽  
Complex Modes ◽  
Firing Properties ◽  
And Function

Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.

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 Effect of Oxaliplatin on Voltage-Gated Sodium Channels in Peripheral Neuropathic Pain

Processes ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 680 ◽  
Author(s):  
Woojin Kim
Keyword(s):  
Neuropathic Pain ◽  
Action Potential ◽  
Sodium Channels ◽  
Sodium Current ◽  
Voltage Response ◽  
Treatment Schedule ◽  
Voltage Gated ◽  
Peripheral Neurons ◽  
Voltage Gated Sodium Channels ◽  
Current Voltage

Oxaliplatin is a chemotherapeutic drug widely used to treat various types of tumors. However, it can induce a serious peripheral neuropathy characterized by cold and mechanical allodynia that can even disrupt the treatment schedule. Since the approval of the agent, many laboratories, including ours, have focused their research on finding a drug or method to decrease this side effect. However, to date no drug that can effectively reduce the pain without causing any adverse events has been developed, and the mechanism of the action of oxaliplatin is not clearly understood. On the dorsal root ganglia (DRG) sensory neurons, oxaliplatin is reported to modify their functions, such as the propagation of the action potential and induction of neuropathic pain. Voltage-gated sodium channels in the DRG neurons are important, as they play a major role in the excitability of the cell by initiating the action potential. Thus, in this small review, eight studies that investigated the effect of oxaliplatin on sodium channels of peripheral neurons have been included. Its effects on the duration of the action potential, peak of the sodium current, voltage–response relationship, inactivation current, and sensitivity to tetrodotoxin (TTX) are discussed.

scholarly journals Chemometric Models of Differential Amino Acids at the Navα and Navβ Interface of Mammalian Sodium Channel Isoforms

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3551
Author(s):  
Fernando Villa-Diaz ◽  
Susana Lopez-Nunez ◽  
Jordan E. Ruiz-Castelan ◽  
Eduardo Marcos Salinas-Stefanon ◽  
Thomas Scior
Keyword(s):  
Sodium Channel ◽  
Sodium Current ◽  
Schematic Model ◽  
Excitable Cells ◽  
Protein Protein Interaction ◽  
Voltage Gated Sodium Channels ◽  
Gating Mechanism ◽  
In Silico Modeling ◽  
Variable Extent ◽  
Domain I

(1) Background: voltage-gated sodium channels (Navs) are integral membrane proteins that allow the sodium ion flux into the excitable cells and initiate the action potential. They comprise an α (Navα) subunit that forms the channel pore and are coupled to one or more auxiliary β (Navβ) subunits that modulate the gating to a variable extent. (2) Methods: after performing homology in silico modeling for all nine isoforms (Nav1.1α to Nav1.9α), the Navα and Navβ protein-protein interaction (PPI) was analyzed chemometrically based on the primary and secondary structures as well as topological or spatial mapping. (3) Results: our findings reveal a unique isoform-specific correspondence between certain segments of the extracellular loops of the Navα subunits. Precisely, loop S5 in domain I forms part of the PPI and assists Navβ1 or Navβ3 on all nine mammalian isoforms. The implied molecular movements resemble macroscopic springs, all of which explains published voltage sensor effects on sodium channel fast inactivation in gating. (4) Conclusions: currently, the specific functions exerted by the Navβ1 or Navβ3 subunits on the modulation of Navα gating remain unknown. Our work determined functional interaction in the extracellular domains on theoretical grounds and we propose a schematic model of the gating mechanism of fast channel sodium current inactivation by educated guessing.

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 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 CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

2017 ◽  
Vol 114 (7) ◽  
pp. 1696-1701 ◽  
Author(s):  
Christopher H. Thompson ◽  
Nicole A. Hawkins ◽  
Jennifer A. Kearney ◽  
Alfred L. George
Keyword(s):  
Sodium Channels ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Focal Epilepsy ◽  
Sodium Current ◽  
Firing Frequency ◽  
Persistent Current ◽  
Clinical Severity ◽  
Persistent Sodium Current ◽  
Channel Inactivation

Monogenic epilepsies with wide-ranging clinical severity have been associated with mutations in voltage-gated sodium channel genes. In the Scn2aQ54 mouse model of epilepsy, a focal epilepsy phenotype is caused by transgenic expression of an engineered NaV1.2 mutation displaying enhanced persistent sodium current. Seizure frequency and other phenotypic features in Scn2aQ54 mice depend on genetic background. We investigated the neurophysiological and molecular correlates of strain-dependent epilepsy severity in this model. Scn2aQ54 mice on the C57BL/6J background (B6.Q54) exhibit a mild disorder, whereas animals intercrossed with SJL/J mice (F1.Q54) have a severe phenotype. Whole-cell recording revealed that hippocampal pyramidal neurons from B6.Q54 and F1.Q54 animals exhibit spontaneous action potentials, but F1.Q54 neurons exhibited higher firing frequency and greater evoked activity compared with B6.Q54 neurons. These findings correlated with larger persistent sodium current and depolarized inactivation in neurons from F1.Q54 animals. Because calcium/calmodulin protein kinase II (CaMKII) is known to modify persistent current and channel inactivation in the heart, we investigated CaMKII as a plausible modulator of neuronal sodium channels. CaMKII activity in hippocampal protein lysates exhibited a strain-dependence in Scn2aQ54 mice with higher activity in F1.Q54 animals. Heterologously expressed NaV1.2 channels exposed to activated CaMKII had enhanced persistent current and depolarized channel inactivation resembling the properties of F1.Q54 neuronal sodium channels. By contrast, inhibition of CaMKII attenuated persistent current, evoked a hyperpolarized channel inactivation, and suppressed neuronal excitability. We conclude that CaMKII-mediated modulation of neuronal sodium current impacts neuronal excitability in Scn2aQ54 mice and may represent a therapeutic target for the treatment of epilepsy.

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