scholarly journals Calmodulin Interactions with Voltage-Gated Sodium Channels

2021 ◽  
Vol 22 (18) ◽  
pp. 9798
Author(s):  
Xin Wu ◽  
Liang Hong
Keyword(s):  
Sodium Channel ◽  
Protein Trafficking ◽  
Sodium Current ◽  
Signal Transducer ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Cellular Electrophysiology ◽  
Voltage Gated Sodium Channels ◽  
Cam Regulation ◽  
Gating Process

Calmodulin (CaM) is a small protein that acts as a ubiquitous signal transducer and regulates neuronal plasticity, muscle contraction, and immune response. It interacts with ion channels and plays regulatory roles in cellular electrophysiology. CaM modulates the voltage-gated sodium channel gating process, alters sodium current density, and regulates sodium channel protein trafficking and expression. Many mutations in the CaM-binding IQ domain give rise to diseases including epilepsy, autism, and arrhythmias by interfering with CaM interaction with the channel. In the present review, we discuss CaM interactions with the voltage-gated sodium channel and modulators involved in CaM regulation, as well as summarize CaM-binding IQ domain mutations associated with human diseases in the voltage-gated sodium channel family.

scholarly journals Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac

2016 ◽  
Vol 113 (48) ◽  
pp. 13762-13767 ◽  
Author(s):  
Monica N. Kinde ◽  
Vasyl Bondarenko ◽  
Daniele Granata ◽  
Weiming Bu ◽  
Kimberly C. Grasty ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Binding Sites ◽  
Ion Selectivity ◽  
Selectivity Filter ◽  
Inactivation Kinetics ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Binding Data ◽  
Quantitative Analyses

Voltage-gated sodium channels (NaV) play an important role in general anesthesia. Electrophysiology measurements suggest that volatile anesthetics such as isoflurane inhibit NaVby stabilizing the inactivated state or altering the inactivation kinetics. Recent computational studies suggested the existence of multiple isoflurane binding sites in NaV, but experimental binding data are lacking. Here we use site-directed placement of19F probes in NMR experiments to quantify isoflurane binding to the bacterial voltage-gated sodium channel NaChBac.19F probes were introduced individually to S129 and L150 near the S4–S5 linker, L179 and S208 at the extracellular surface, T189 in the ion selectivity filter, and all phenylalanine residues. Quantitative analyses of19F NMR saturation transfer difference (STD) spectroscopy showed a strong interaction of isoflurane with S129, T189, and S208; relatively weakly with L150; and almost undetectable with L179 and phenylalanine residues. An orientation preference was observed for isoflurane bound to T189 and S208, but not to S129 and L150. We conclude that isoflurane inhibits NaChBac by two distinct mechanisms: (i) as a channel blocker at the base of the selectivity filter, and (ii) as a modulator to restrict the pivot motion at the S4–S5 linker and at a critical hinge that controls the gating and inactivation motion of S6.

scholarly journals Rapid evolution of a voltage-gated sodium channel gene in a lineage of electric fish leads to a persistent sodium current

PLoS Biology ◽  
2018 ◽  
Vol 16 (3) ◽  
pp. e2004892 ◽  
Author(s):  
Ammon Thompson ◽  
Daniel T. Infield ◽  
Adam R. Smith ◽  
G. Troy Smith ◽  
Christopher A. Ahern ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Electric Fish ◽  
Sodium Current ◽  
Rapid Evolution ◽  
Persistent Sodium Current ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Channel Gene ◽  
Sodium Channel Gene

scholarly journals Nedd4-2 (NEDD4L) controls intracellular Na+-mediated activity of voltage-gated sodium channels in primary cortical neurons

2013 ◽  
Vol 457 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Jenny A. Ekberg ◽  
Natasha A. Boase ◽  
Grigori Rychkov ◽  
Jantina Manning ◽  
Philip Poronnik ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
Ubiquitin Ligase ◽  
Cortical Neurons ◽  
Channel Activity ◽  
Primary Cortical Neurons ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
First Time

The study shows for the first time that the ubiquitin ligase Nedd4-2 regulates voltage-gated sodium channel activity in cortical neurons, specifically in response to elevated intracellular Na+ concentration.

scholarly journals Solution Structure and Alanine Scan of a Spider Toxin That Affects the Activation of Mammalian Voltage-gated Sodium Channels

2006 ◽  
Vol 282 (7) ◽  
pp. 4643-4652 ◽  
Author(s):  
Gerardo Corzo ◽  
Jennifer K. Sabo ◽  
Frank Bosmans ◽  
Bert Billen ◽  
Elba Villegas ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Channels ◽  
Solution Structure ◽  
Receptor Site ◽  
Amino Acid Sequences ◽  
Structural Motif ◽  
Dimensional Structure ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

Magi 5, from the hexathelid spider Macrothele gigas, is a 29-residue polypeptide containing three disulfide bridges. It binds specifically to receptor site 4 on mammalian voltage-gated sodium channels and competes with scorpion β-toxins, such as Css IV from Centruroides suffusus suffusus. As a consequence, Magi 5 shifts the activation voltage of the mammalian rNav1.2a channel to more hyperpolarized voltages, whereas the insect channel, DmNav1, is not affected. To gain insight into toxin-channel interactions, Magi 5 and 23 analogues were synthesized. The three-dimensional structure of Magi 5 in aqueous solution was determined, and its voltage-gated sodium channel-binding surfaces were mapped onto this structure using data from electrophysiological measurements on a series of Ala-substituted analogues. The structure clearly resembles the inhibitor cystine knot structural motif, although the triple-stranded β-sheet typically found in that motif is partially distorted in Magi 5. The interactive surface of Magi 5 toward voltage-gated sodium channels resembles in some respects the Janus-faced atracotoxins, with functionally important charged residues on one face of the toxin and hydrophobic residues on the other. Magi 5 also resembles the scorpion β-toxin Css IV, which has distinct nonpolar and charged surfaces that are critical for channel binding and has a key Glu involved in voltage sensor trapping. These two distinct classes of toxin, with different amino acid sequences and different structures, may utilize similar groups of residues on their surface to achieve the common end of modifying voltage-gated sodium channel function.

scholarly journals Kinetic and thermodynamic modeling of a voltage-gated sodium channel

2021 ◽  
Author(s):  
Mara Almog ◽  
Nurit Degani-Katzav ◽  
Alon Korngreen
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Sodium Channel ◽  
Temperature Dependence ◽  
Cortical Neurons ◽  
Room Temperature ◽  
Pyramidal Neurons ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

Like all biological and chemical reactions, ion channel kinetics are highly sensitive to changes in temperature. Therefore, it is prudent to investigate channel dynamics at physiological temperatures. However, most ion channel investigations are performed at room temperature due to practical considerations, such as recording stability and technical limitations. This problem is especially severe for the fast voltage-gated sodium channel, whose activation kinetics are faster than the time constant of the standard patch-clamp amplifier at physiological temperatures. Thus, biologically detailed simulations of the action potential generation evenly scale the kinetic models of voltage-gated channels acquired at room temperature. To quantitatively study voltage-gated sodium channels' temperature sensitivity, we recorded sodium currents from nucleated patches extracted from the rat's layer five neocortical pyramidal neurons at several temperatures from 13.5 to 30°C. We use these recordings to model the kinetics of the voltage-gated sodium channel as a function of temperature. We show that the temperature dependence of activation differs from that of inactivation. Furthermore, we show that the sustained current has a different temperature dependence than the fast current. Our kinetic and thermodynamic analysis of the current provided a numerical model spanning the entire temperature range. This model reproduced vital features of channel activation and inactivation. Furthermore, the model also reproduced action potential dependence on temperature. Thus, we provide an essential building block for the generation of biologically detailed models of cortical neurons.

scholarly journals Structures of closed and open states of a voltage-gated sodium channel

2017 ◽  
Vol 114 (15) ◽  
pp. E3051-E3060 ◽  
Author(s):  
Michael J. Lenaeus ◽  
Tamer M. Gamal El-Din ◽  
Christopher Ing ◽  
Karthik Ramanadane ◽  
Régis Pomès ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Full Range ◽  
Structural Basis ◽  
Ion Permeation ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Mechanism ◽  
Activation Gate ◽  
Open States

Bacterial voltage-gated sodium channels (BacNavs) serve as models of their vertebrate counterparts. BacNavs contain conserved voltage-sensing and pore-forming domains, but they are homotetramers of four identical subunits, rather than pseudotetramers of four homologous domains. Here, we present structures of two NaVAb mutants that capture tightly closed and open states at a resolution of 2.8–3.2 Å. Introduction of two humanizing mutations in the S6 segment (NaVAb/FY: T206F and V213Y) generates a persistently closed form of the activation gate in which the intracellular ends of the four S6 segments are drawn tightly together to block ion permeation completely. This construct also revealed the complete structure of the four-helix bundle that forms the C-terminal domain. In contrast, truncation of the C-terminal 40 residues in NavAb/1–226 captures the activation gate in an open conformation, revealing the open state of a BacNav with intact voltage sensors. Comparing these structures illustrates the full range of motion of the activation gate, from closed with its orifice fully occluded to open with an orifice of ∼10 Å. Molecular dynamics and free-energy simulations confirm designation of NaVAb/1–226 as an open state that allows permeation of hydrated Na+, and these results also support a hydrophobic gating mechanism for control of ion permeation. These two structures allow completion of a closed–open–inactivated conformational cycle in a single voltage-gated sodium channel and give insight into the structural basis for state-dependent binding of sodium channel-blocking drugs.

scholarly journals Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 297 ◽  
Author(s):  
Tomas Koltai
Keyword(s):  
Sodium Channel ◽  
Daily Practice ◽  
Clinical Settings ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Metastatic Activity ◽  
Repurposed Drugs ◽  
Metastatic Risk

Objective: To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties.Material and methods: A review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it was tested with this purpose in the experimental and clinical settings.Results: The following pharmaceuticals that fulfill the above mentioned effects, were found: phenytoin, carbamazepine, valproate, lamotrigine, ranolazine, resveratrol, ropivacaine, lidocaine, mexiletine, flunarizine, and riluzole. Each of them are independently described and analyzed.Conclusions: The above mentioned pharmaceuticals have shown anti-metastatic and anti-invasion activity and many of them deserve to be tested in well-planned clinical trials as adjunct therapies for solid tumors and as anti-metastatic agents. Antiepileptic drugs like phenytoin, carbamazepine and valproate and the vasodilator flunarizine emerged as particularly useful for anti-metastatic purposes.

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
Sign in / Sign up

Export Citation Format

Share Document