scholarly journals Role of the Local Anesthetic Receptor in the State-Dependent Inhibition of Voltage-Gated Sodium Channels by the Insecticide Metaflumizone

2011 ◽  
Vol 81 (3) ◽  
pp. 366-374 ◽  
Author(s):  
Richard T. von Stein ◽  
David M. Soderlund
Keyword(s):  
Sodium Channels ◽  
Local Anesthetic ◽  
The State ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Dependent Inhibition

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 Mining the Virgin Land of Neurotoxicology: A Novel Paradigm of Neurotoxic Peptides Action on Glycosylated Voltage-Gated Sodium Channels

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Zhirui Liu ◽  
Jie Tao ◽  
Pin Ye ◽  
Yonghua Ji
Keyword(s):  
Sodium Channels ◽  
Network Activity ◽  
Voltage Gated ◽  
Virgin Land ◽  
Neuronal Network Activity ◽  
Voltage Gated Sodium Channels ◽  
Pharmacological Targets ◽  
Underlying Mechanisms ◽  
Posttranslation Modification

Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs.

The Role of Nonprotein Domains in the Function and Synthesis of Voltage-Gated Sodium Channels

Ion Channels ◽  
1990 ◽  
pp. 33-64 ◽  
Author(s):  
S. R. Levinson ◽  
W. B. Thornhill ◽  
D. S. Duch ◽  
E. Recio-Pinto ◽  
B. W. Urban
Keyword(s):  
Sodium Channels ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

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.

scholarly journals The Emerging Role of Voltage-Gated Sodium Channels in Tumor Biology

2019 ◽  
Vol 9 ◽  
Author(s):  
Weijia Mao ◽  
Jie Zhang ◽  
Heinrich Körner ◽  
Yong Jiang ◽  
Songcheng Ying
Keyword(s):  
Sodium Channels ◽  
Tumor Biology ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Electrostatic Contributions of Aromatic Residues in the Local Anesthetic Receptor of Voltage-Gated Sodium Channels

2008 ◽  
Vol 102 (1) ◽  
pp. 86-94 ◽  
Author(s):  
Christopher A. Ahern ◽  
Amy L. Eastwood ◽  
Dennis A. Dougherty ◽  
Richard Horn
Keyword(s):  
Sodium Channels ◽  
Local Anesthetic ◽  
Aromatic Residues ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Neuropathic Pain Develops Normally in Mice Lacking both Nav1.7 and Nav1.8

2005 ◽  
Vol 1 ◽  
pp. 1744-8069-1-24 ◽  
Author(s):  
Mohammed A Nassar ◽  
Alessandra Levato ◽  
L Caroline Stirling ◽  
John N Wood
Keyword(s):  
Neuropathic Pain ◽  
Sodium Channels ◽  
Sensory Neurons ◽  
Inflammatory Pain ◽  
Pain Thresholds ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Pain Symptoms ◽  
Α Subunits

Two voltage gated sodium channel α-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Nav1.7 and Nav1.8 is uncertain. Here we show that deleting Nav1.7 has no effect on the development of neuropathic pain. Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Nav1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Nav1.7 or Nav1.8 alone or in combination.

Role of submembranous actin cytoskeleton in regulation of non-voltage-gated sodium channels

2013 ◽  
Vol 450 (1) ◽  
pp. 126-129
Author(s):  
V. I. Chubinskiy-Nadezhdin ◽  
A. V. Sudarikova ◽  
N. N. Nikolsky ◽  
E. A. Morachevskaya
Keyword(s):  
Actin Cytoskeleton ◽  
Sodium Channels ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes

2018 ◽  
Vol 293 (23) ◽  
pp. 9041-9052 ◽  
Author(s):  
Akello J. Agwa ◽  
Steve Peigneur ◽  
Chun Yuen Chow ◽  
Nicole Lawrence ◽  
David J. Craik ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Lipid Membranes ◽  
Spider Venom ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Modifier
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