scholarly journals Atomic determinants of state-dependent block of sodium channels by charged local anesthetics and benzocaine

FEBS Letters ◽  
2006 ◽  
Vol 580 (26) ◽  
pp. 6027-6032 ◽  
Author(s):  
Denis B. Tikhonov ◽  
Iva Bruhova ◽  
Boris S. Zhorov
Keyword(s):  
Sodium Channels ◽  
Local Anesthetics ◽  
State Dependent

Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design

2018 ◽  
Vol 46 (6) ◽  
pp. 1567-1575 ◽  
Author(s):  
Giulia Montini ◽  
Jennifer Booker ◽  
Altin Sula ◽  
B.A. Wallace
Keyword(s):  
Drug Design ◽  
Sodium Channels ◽  
Rational Drug Design ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Rational Drug ◽  
Sequence Homologies ◽  
Arcobacter Butzleri ◽  
Functional Consequences

Voltage-gated sodium channels (Navs) are responsible for the initiation of the action potential in excitable cells. Several prokaryotic sodium channels, most notably NavMs from Magnetococcus marinus and NavAb from Arcobacter butzleri, have been shown to be good models for human sodium channels based on their sequence homologies and high levels of functional similarities, including ion flux, and functional consequences of critical mutations. The complete full-length crystal structures of these prokaryotic sodium channels captured in different functional states have now revealed the molecular natures of changes associated with the gating process. These include the structures of the intracellular gate, the selectivity filter, the voltage sensors, the intra-membrane fenestrations, and the transmembrane (TM) pore. Here we have identified for the first time how changes in the fenestrations in the hydrophobic TM region associated with the opening of the intracellular gate could modulate the state-dependent ingress and binding of drugs in the TM cavity, in a way that could be exploited for rational drug design.

scholarly journals Local Anesthetics Disrupt Energetic Coupling between the Voltage-sensing Segments of a Sodium Channel

2008 ◽  
Vol 133 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Yukiko Muroi ◽  
Baron Chanda
Keyword(s):  
Sodium Channel ◽  
Local Anesthetic ◽  
Local Anesthetics ◽  
Quantitative Description ◽  
Single Mutation ◽  
Voltage Sensing ◽  
State Behavior ◽  
Fluorescence Measurements ◽  
State Dependent ◽  
Domain Iii

Local anesthetics block sodium channels in a state-dependent fashion, binding with higher affinity to open and/or inactivated states. Gating current measurements show that local anesthetics immobilize a fraction of the gating charge, suggesting that the movement of voltage sensors is modified when a local anesthetic binds to the pore of the sodium channel. Here, using voltage clamp fluorescence measurements, we provide a quantitative description of the effect of local anesthetics on the steady-state behavior of the voltage-sensing segments of a sodium channel. Lidocaine and QX-314 shifted the midpoints of the fluorescence–voltage (F-V) curves of S4 domain III in the hyperpolarizing direction by 57 and 65 mV, respectively. A single mutation in the S6 of domain IV (F1579A), a site critical for local anesthetic block, abolished the effect of QX-314 on the voltage sensor of domain III. Both local anesthetics modestly shifted the F-V relationships of S4 domain IV toward hyperpolarized potentials. In contrast, the F-V curve of the S4 domain I was shifted by 11 mV in the depolarizing direction upon QX-314 binding. These antagonistic effects of the local anesthetic indicate that the drug modifies the coupling between the voltage-sensing domains of the sodium channel. Our findings suggest a novel role of local anesthetics in modulating the gating apparatus of the sodium channel.

Inhibition of Nav1.7 and Nav1.4 Sodium Channels by Trifluoperazine Involves the Local Anesthetic Receptor

2006 ◽  
Vol 96 (4) ◽  
pp. 1848-1859 ◽  
Author(s):  
Patrick L. Sheets ◽  
Peter Gerner ◽  
Chi-Fei Wang ◽  
Sho-Ya Wang ◽  
Ging Kuo Wang ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Local Anesthetic ◽  
Receptor Site ◽  
Inhibitory Peptide ◽  
Sensory Blockade ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Steady State Inactivation ◽  
Channel Interactions

The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats; however, the mechanism is not known. We asked whether TFP could modulate the Nav1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 μM TFP induce major decreases in Nav1.7 and Nav1.4 current amplitudes and that 2 μM TFP causes hyperpolarizing shifts in the steady-state inactivation of Nav1.7 and Nav1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data show that TFP inhibition is state dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Nav1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogues, might be useful for regional anesthesia and pain management and could be more potent than traditional local anesthetics.

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.

LOCAL ANESTHETICS MANIFEST TWO DISTINCT MODES OF BLOCKADE OF SINGLE SODIUM CHANNELS

1991 ◽  
Vol 75 (3) ◽  
pp. A687-A687
Author(s):  
K. Gingrich ◽  
D. Beardsley ◽  
D. Yue
Keyword(s):  
Sodium Channels ◽  
Local Anesthetics ◽  
Single Sodium Channels
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