scholarly journals Flufenamic acid decreases neuronal excitability through modulation of voltage-gated sodium channel gating

2010 ◽  
Vol 588 (20) ◽  
pp. 3869-3882 ◽  
Author(s):  
Hau-Jie Yau ◽  
Gytis Baranauskas ◽  
Marco Martina
Keyword(s):  
Sodium Channel ◽  
Neuronal Excitability ◽  
Channel Gating ◽  
Flufenamic Acid ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

scholarly journals Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants

2020 ◽  
Vol 152 (3) ◽  
Author(s):  
Christopher H. Thompson ◽  
Roy Ben-Shalom ◽  
Kevin J. Bender ◽  
Alfred L. George
Keyword(s):  
Alternative Splicing ◽  
Sodium Channel ◽  
Early Onset ◽  
Neuronal Excitability ◽  
Epileptic Encephalopathy ◽  
Developmentally Regulated ◽  
Voltage Gated Sodium Channel ◽  
Splice Isoforms ◽  
Voltage Gated ◽  
Splice Isoform

Epileptic encephalopathies are severe forms of infantile-onset epilepsy often complicated by severe neurodevelopmental impairments. Some forms of early-onset epileptic encephalopathy (EOEE) have been associated with variants in SCN2A, which encodes the brain voltage-gated sodium channel NaV1.2. Many voltage-gated sodium channel genes, including SCN2A, undergo developmentally regulated mRNA splicing. The early onset of these disorders suggests that developmentally regulated alternative splicing of NaV1.2 may be an important consideration when elucidating the pathophysiological consequences of epilepsy-associated variants. We hypothesized that EOEE-associated NaV1.2 variants would exhibit greater dysfunction in a splice isoform that is prominently expressed during early development. We engineered five EOEE-associated NaV1.2 variants (T236S, E999K, S1336Y, T1623N, and R1882Q) into the adult and neonatal splice isoforms of NaV1.2 and performed whole-cell voltage clamp to elucidate their functional properties. All variants exhibited functional defects that could enhance neuronal excitability. Three of the five variants (T236S, E999K, and S1336Y) exhibited greater dysfunction in the neonatal isoform compared with those observed in the adult isoform. Computational modeling of a developing cortical pyramidal neuron indicated that T236S, E999K, S1336Y, and R1882Q showed hyperexcitability preferentially in immature neurons. These results suggest that both splice isoform and neuronal developmental stage influence how EOEE-associated NaV1.2 variants affect neuronal excitability.

scholarly journals Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

2021 ◽  
Author(s):  
Jingliang Zhang ◽  
Xiaoling Chen ◽  
Muriel Eaton ◽  
Shirong Lai ◽  
Anthony Park ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Sodium Channel ◽  
Neuronal Excitability ◽  
Brain Slices ◽  
List Type ◽  
Voltage Gated Sodium Channel ◽  
Neuronal Hyperexcitability ◽  
Voltage Gated ◽  
Adult Mice ◽  
Mechanistic Investigation

AbstractScn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.TEASERSevere NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels.HIGHLIGHTSSevere NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice;Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold;NaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous;The expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability;The enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures.

scholarly journals CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability

2020 ◽  
Vol 295 (33) ◽  
pp. 11845-11865
Author(s):  
Agnes S. Zybura ◽  
Anthony J. Baucum ◽  
Anthony M. Rush ◽  
Theodore R. Cummins ◽  
Andy Hudmon
Keyword(s):  
Protein Kinase ◽  
Sodium Channel ◽  
Neuronal Excitability ◽  
Cell Model ◽  
Site Directed Mutagenesis ◽  
Hek293 Cells ◽  
Intracellular Loop ◽  
Persistent Currents ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

Nav1.6 is the primary voltage-gated sodium channel isoform expressed in mature axon initial segments and nodes, making it critical for initiation and propagation of neuronal impulses. Thus, Nav1.6 modulation and dysfunction may have profound effects on input-output properties of neurons in normal and pathological conditions. Phosphorylation is a powerful and reversible mechanism regulating ion channel function. Because Nav1.6 and the multifunctional Ca2+/CaM-dependent protein kinase II (CaMKII) are independently linked to excitability disorders, we sought to investigate modulation of Nav1.6 function by CaMKII signaling. We show that inhibition of CaMKII, a Ser/Thr protein kinase associated with excitability, synaptic plasticity, and excitability disorders, with the CaMKII-specific peptide inhibitor CN21 reduces transient and persistent currents in Nav1.6-expressing Purkinje neurons by 87%. Using whole-cell voltage clamp of Nav1.6, we show that CaMKII inhibition in ND7/23 and HEK293 cells significantly reduces transient and persistent currents by 72% and produces a 5.8-mV depolarizing shift in the voltage dependence of activation. Immobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. Using site-directed mutagenesis to test multiple potential sites of phosphorylation, we show that Ala substitutions of Ser-561 and Ser-641/Thr-642 recapitulate the depolarizing shift in activation and reduction in current density. Computational simulations to model effects of CaMKII inhibition on Nav1.6 function demonstrate dramatic reductions in spontaneous and evoked action potentials in a Purkinje cell model, suggesting that CaMKII modulation of Nav1.6 may be a powerful mechanism to regulate neuronal excitability.

scholarly journals Severe deficiency of the voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Cell Reports ◽  
2021 ◽  
Vol 36 (5) ◽  
pp. 109495
Author(s):  
Jingliang Zhang ◽  
Xiaoling Chen ◽  
Muriel Eaton ◽  
Jiaxiang Wu ◽  
Zhixiong Ma ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Neuronal Excitability ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Adult Mice ◽  
Severe Deficiency

scholarly journals Differential Sialylation Modulates Voltage-gated Na+ Channel Gating throughout the Developing Myocardium

2006 ◽  
Vol 127 (3) ◽  
pp. 253-265 ◽  
Author(s):  
Patrick J. Stocker ◽  
Eric S. Bennett
Keyword(s):  
Sialic Acid ◽  
Sodium Channel ◽  
Channel Gating ◽  
Sialic Acids ◽  
Na Channel ◽  
Voltage Gated Sodium Channel ◽  
Α Subunit ◽  
Rat Cardiomyocytes ◽  
Voltage Gated ◽  
Α Subunits

Voltage-gated sodium channel function from neonatal and adult rat cardiomyocytes was measured and compared. Channels from neonatal ventricles required an ∼10 mV greater depolarization for voltage-dependent gating events than did channels from neonatal atria and adult atria and ventricles. We questioned whether such gating shifts were due to developmental and/or chamber-dependent changes in channel-associated functional sialic acids. Thus, all gating characteristics for channels from neonatal atria and adult atria and ventricles shifted significantly to more depolarized potentials after removal of surface sialic acids. Desialylation of channels from neonatal ventricles did not affect channel gating. After removal of the complete surface N-glycosylation structures, gating of channels from neonatal atria and adult atria and ventricles shifted to depolarized potentials nearly identical to those measured for channels from neonatal ventricles. Gating of channels from neonatal ventricles were unaffected by such deglycosylation. Immunoblot gel shift analyses indicated that voltage-gated sodium channel α subunits from neonatal atria and adult atria and ventricles are more heavily sialylated than α subunits from neonatal ventricles. The data are consistent with approximately 15 more sialic acid residues attached to each α subunit from neonatal atria and adult atria and ventricles. The data indicate that differential sialylation of myocyte voltage-gated sodium channel α subunits is responsible for much of the developmental and chamber-specific remodeling of channel gating observed here. Further, cardiac excitability is likely impacted by these sialic acid–dependent gating effects, such as modulation of the rate of recovery from inactivation. A novel mechanism is described by which cardiac voltage-gated sodium channel gating and subsequently cardiac rhythms are modulated by changes in channel-associated sialic acids.

scholarly journals Elevated Neuronal Excitability Due to Modulation of the Voltage-Gated Sodium Channel Nav1.6 by Aβ1−42

2016 ◽  
Vol 10 ◽  
Author(s):  
Xi Wang ◽  
Xiao-Gang Zhang ◽  
Ting-Ting Zhou ◽  
Na Li ◽  
Chun-Yan Jang ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Neuronal Excitability ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

The Voltage-Gated Sodium Channel Nav1.2 Contributes to Neurodegeneration in an Animal Model of Multiple Sclerosis

2016 ◽  
Vol 47 (S 01) ◽  
Author(s):  
W. Fazeli ◽  
B. Schattling ◽  
B. Engeland ◽  
M. Friese ◽  
D. Isbrand
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Sodium Channel ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated
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