Molecular determinants of prokaryotic voltage-gated sodium channels for recognition of local anesthetics

FEBS Journal ◽  
2016 ◽  
Vol 283 (15) ◽  
pp. 2881-2895 ◽  
Author(s):  
Takushi Shimomura ◽  
Katsumasa Irie ◽  
Yoshinori Fujiyoshi
Keyword(s):  
Sodium Channels ◽  
Local Anesthetics ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Molecular Determinants

Spectral Investigations, Molecular Interactions and Electrochemical Studies of (2R)-(-)2-(2, 6-dimethylphenylaminocarbonyl)-1-methyl Piperidinium Chloride

2020 ◽  
Vol 15 (4) ◽  
pp. 358-368
Author(s):  
J. Deva Anban ◽  
J. Sharmi Kumar ◽  
C. James ◽  
Sayantan Pradhan
Keyword(s):  
Sodium Channels ◽  
Local Anesthetics ◽  
Natural Bond Orbital ◽  
Nbo Analysis ◽  
Basis Set ◽  
Voltage Gated ◽  
Peripheral Neurons ◽  
Voltage Gated Sodium Channels ◽  
Title Molecule ◽  
Inner Pore

Background: Local anesthetics are widely used to decrease sensitivity to pain in specific regions of the body while performing medical tasks. Many studies have probed the mechanism of action of local anesthetics but still many questions remain. (2R - (-) 2 - (2, 6-dimethylphenylaminocarbonyl) - 1 – methyl piperidinium chloride (DAMP), is an extensively used amide-type local anesthetic. Objective: This study aims at revealing the various electrophysical and chemical properties of the title compound. This study will be useful for future research by pharmacologists. Method: Density Functional Theory (DFT) computations were executed using Gaussian’09 program package and were optimized with the B3LYP /6-311+G (d, p) basis set. Natural bond orbital (NBO) analysis was carried out with version 3.1. Normal Coordinate Analysis (NCA) was used to systematically calculate the harmonic vibrational wavenumbers. Molecular docking simulations were carried out to understand the pharmacokinetic behavior of the drug. Results: The presence of strong N-H…Cl intra molecular hydrogen bonding was evidently revealed from the FT-IR spectrum due to the shifting of NH stretching wavenumber. Stability of the molecule arising from hyper conjugative interactions exhibits the bioactivity of the molecule by natural bond orbital analysis. The title molecule binds to the inner pore and blocks voltage - gated sodium channels in peripheral neurons. Conclusion: A detailed molecular picture of DAMP and its interactions were obtained by modeling analysis, IR, Raman, and UV-Vis spectroscopy. The geometrical parameters agree well with the XRD data. NBO analysis indicates the bioactivity of the molecule. The HOMO-LUMO energy gap indicates the possibility of intramolecular charge transfer of the molecule. From the ligand docking studies it is concluded that the title molecule binds to the inner pore and blocks voltage - gated sodium channels in peripheral neurons.

scholarly journals Molecular Determinants of μ-Conotoxin KIIIA Block of Voltage-Gated Sodium Channels

2009 ◽  
Vol 96 (3) ◽  
pp. 248a ◽  
Author(s):  
Jeff R. McArthur ◽  
Min-min Zhang ◽  
Layla Azam ◽  
Songjiang Luo ◽  
Baldomero M. Olivera ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Molecular Determinants

Molecular determinants for the subtype specificity of μ-conotoxin SIIIA targeting neuronal voltage-gated sodium channels

2011 ◽  
Vol 61 (1-2) ◽  
pp. 105-111 ◽  
Author(s):  
Enrico Leipold ◽  
René Markgraf ◽  
Alesia Miloslavina ◽  
Michael Kijas ◽  
Jana Schirmeyer ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Subtype Specificity ◽  
Molecular Determinants

scholarly journals Molecular Determinants of Human Voltage-Gated Sodium Channels Blockade by Lubeluzole

2012 ◽  
Vol 102 (3) ◽  
pp. 323a
Author(s):  
Jean-François Desaphy ◽  
Teresa Costanza ◽  
Roberta Carbonara ◽  
Maria Maddalena Cavalluzzi ◽  
Carlo Franchini ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Molecular Determinants

scholarly journals Molecular determinants of state-dependent block of voltage-gated sodium channels by pilsicainide

2010 ◽  
Vol 160 (6) ◽  
pp. 1521-1533 ◽  
Author(s):  
J-F Desaphy ◽  
A Dipalma ◽  
T Costanza ◽  
C Bruno ◽  
G Lentini ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Molecular Determinants

scholarly journals Molecular Determinants of Brevetoxin Binding to Voltage-Gated Sodium Channels

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 513 ◽  
Author(s):  
Keiichi Konoki ◽  
Daniel G. Baden ◽  
Todd Scheuer ◽  
William A. Catterall
Keyword(s):  
Sodium Channels ◽  
Red Tides ◽  
Shellfish Poisoning ◽  
Alanine Scanning Mutagenesis ◽  
Α Subunit ◽  
Voltage Gated ◽  
Transmembrane Segments ◽  
Voltage Gated Sodium Channels ◽  
Fold Reduction ◽  
Molecular Determinants

Brevetoxins are produced by dinoflagellates such as Karenia brevis in warm-water red tides and cause neurotoxic shellfish poisoning. They bind to voltage-gated sodium channels at neurotoxin receptor 5, making the channels more active by shifting the voltage-dependence of activation to more negative potentials and by slowing the inactivation process. Previous work using photoaffinity labeling identified binding to the IS6 and IVS5 transmembrane segments of the channel α subunit. We used alanine-scanning mutagenesis to identify molecular determinants for brevetoxin binding in these regions as well as adjacent regions IVS5-SS1 and IVS6. Most of the mutant channels containing single alanine substitutions expressed functional protein in tsA-201 cells and bound to the radioligand [42-3H]-PbTx3. Binding affinity for the great majority of mutant channels was indistinguishable from wild type. However, transmembrane segments IS6, IVS5 and IVS6 each contained 2 to 4 amino acid positions where alanine substitution resulted in a 2–3-fold reduction in brevetoxin affinity, and additional mutations caused a similar increase in brevetoxin affinity. These findings are consistent with a model in which brevetoxin binds to a protein cleft comprising transmembrane segments IS6, IVS5 and IVS6 and makes multiple distributed interactions with these α helices. Determination of brevetoxin affinity for Nav1.2, Nav1.4 and Nav1.5 channels showed that Nav1.5 channels had a characteristic 5-fold reduction in affinity for brevetoxin relative to the other channel isoforms, suggesting the interaction with sodium channels is specific despite the distributed binding determinants.

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