scholarly journals Volatile anesthetics inhibit sodium channels without altering bulk lipid bilayer properties

2014 ◽  
Vol 144 (6) ◽  
pp. 545-560 ◽  
Author(s):  
Karl F. Herold ◽  
R. Lea Sanford ◽  
William Lee ◽  
Margaret F. Schultz ◽  
Helgi I. Ingólfsson ◽  
...  
Keyword(s):  
Ion Channel ◽  
Lipid Bilayer ◽  
Sodium Channels ◽  
Molecular Mechanisms ◽  
Volatile Anesthetics ◽  
Specific Protein ◽  
Functional Assay ◽  
General Anesthetics ◽  
Voltage Gated Sodium Channels ◽  
Clinical Anesthesia

Although general anesthetics are clinically important and widely used, their molecular mechanisms of action remain poorly understood. Volatile anesthetics such as isoflurane (ISO) are thought to alter neuronal function by depressing excitatory and facilitating inhibitory neurotransmission through direct interactions with specific protein targets, including voltage-gated sodium channels (Nav). Many anesthetics alter lipid bilayer properties, suggesting that ion channel function might also be altered indirectly through effects on the lipid bilayer. We compared the effects of ISO and of a series of fluorobenzene (FB) model volatile anesthetics on Nav function and lipid bilayer properties. We examined the effects of these agents on Nav in neuronal cells using whole-cell electrophysiology, and on lipid bilayer properties using a gramicidin-based fluorescence assay, which is a functional assay for detecting changes in lipid bilayer properties sensed by a bilayer-spanning ion channel. At clinically relevant concentrations (defined by the minimum alveolar concentration), both the FBs and ISO produced prepulse-dependent inhibition of Nav and shifted the voltage dependence of inactivation toward more hyperpolarized potentials without affecting lipid bilayer properties, as sensed by gramicidin channels. Only at supra-anesthetic (toxic) concentrations did ISO alter lipid bilayer properties. These results suggest that clinically relevant concentrations of volatile anesthetics alter Nav function through direct interactions with the channel protein with little, if any, contribution from changes in bulk lipid bilayer properties. Our findings further suggest that changes in lipid bilayer properties are not involved in clinical anesthesia.

Functional Assay of Voltage-Gated Sodium Channels Using Membrane Potential-Sensitive Dyes

2004 ◽  
Vol 2 (3) ◽  
pp. 260-268 ◽  
Author(s):  
John P. Felix ◽  
Brande S. Williams ◽  
Birgit T. Priest ◽  
Richard M. Brochu ◽  
Ivy E. Dick ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Sodium Channels ◽  
Functional Assay ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles

2017 ◽  
Vol 117 (4) ◽  
pp. 1690-1701 ◽  
Author(s):  
Dario I. Carrasco ◽  
Jacob A. Vincent ◽  
Timothy C. Cope
Keyword(s):  
Sodium Channels ◽  
Molecular Mechanisms ◽  
Mammalian Species ◽  
Muscle Spindles ◽  
Tonic Firing ◽  
Muscle Stretch ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Nav Channels ◽  
Sensory Endings

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV1.1, predominantly in sensory terminals together with NaV1.6 and for NaV1.7, mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles. NEW & NOTEWORTHY The molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site involved in transduction or encoding of muscle stretch. We propose that NaVs contribute to multiple steps in sensory signaling by muscle spindles as it does in other types of slowly adapting sensory neurons.

scholarly journals Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

2021 ◽  
Vol 12 ◽  
Author(s):  
Ibitayo Abigail Ademuwagun ◽  
Solomon Oladapo Rotimi ◽  
Steffen Syrbe ◽  
Yvonne Ukamaka Ajamma ◽  
Ezekiel Adebiyi
Keyword(s):  
Ion Channel ◽  
Sodium Channel ◽  
Sodium Channels ◽  
De Novo ◽  
Single Gene ◽  
Voltage Gated ◽  
Functional Studies ◽  
Voltage Gated Sodium Channels ◽  
Genomic Studies ◽  
The Brain

Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

scholarly journals Volatile Anesthetics Regulate Anti-Cancer Relevant Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Shen Sun ◽  
Shaoqiang Huang
Keyword(s):  
Molecular Mechanisms ◽  
Volatile Anesthetics ◽  
Underlying Mechanism ◽  
Research Progress ◽  
Inhalation Anesthetics ◽  
Anti Cancer ◽  
Clinical Anesthesia ◽  
Anesthesia Procedure

Volatile anesthetics are widely used inhalation anesthetics in clinical anesthesia. In recent years, the regulation of anti-cancer relevant signaling of volatile anesthetics has drawn the attention of investigators. However, their underlying mechanism remains unclear. This review summarizes the research progress on the regulation of anti-cancer relevant signaling of volatile anesthetics, including sevoflurane, desflurane, xenon, isoflurane, and halothane in vitro, in vivo, and clinical studies. The present review article aims to provide a general overview of regulation of anti-cancer relevant signaling and explore potential underlying molecular mechanisms of volatile anesthetics. It may promote promising insights of guiding clinical anesthesia procedure and instructing enhance recovery after surgery (ERAS) with latent benefits.

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