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Search Results: 1 - 10 of 8053 matches for " voltage-gated sodium channel "
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Anestésicos locais: intera??o com membranas biológicas e com o canal de sódio voltagem-dependente
Araujo, Daniele Ribeiro de;Paula, Eneida de;Fraceto, Leonardo Fernandes;
Química Nova , 2008, DOI: 10.1590/S0100-40422008000700032
Abstract: many theories about the mechanism of action of local anesthetics (la) are described in the literature. two types of theories can be distinguished: those that focus on the direct effects of la on their target protein in the axon membranes, i.e. the voltage-gated sodium channel and the ones that take into account the interaction of anesthetic molecules with the lipid membrane phase for the reversible nerve blockage. since there is a direct correlation between la hydrophobicity and potency, it is crucial to take this physico-chemical property into account to understand the mechanism of action of la, be it on the sodium channel protein, lipid(s), or on the whole membrane phase.
Regulatory Role of Voltage-Gated Na+ Channel β Subunits in Sensory Neurons
Mohamed Chahine,Michael E. O’Leary
Frontiers in Pharmacology , 2011, DOI: 10.3389/fphar.2011.00070
Abstract: Voltage-gated sodium Na+ channels are membrane-bound proteins incorporating aqueous conduction pores that are highly selective for sodium Na+ ions. The opening of these channels results in the rapid influx of Na+ ions that depolarize the cell and drive the rapid upstroke of nerve and muscle action potentials. While the concept of a Na+-selective ion channel had been formulated in the 1940s, it was not until the 1980s that the biochemical properties of the 260-kDa and 36-kDa auxiliary β subunits (β1, β2) were first described. Subsequent cloning and heterologous expression studies revealed that the α subunit forms the core of the channel and is responsible for both voltage-dependent gating and ionic selectivity. To date, 10 isoforms of the Na+ channel α subunit have been identified that vary in their primary structures, tissue distribution, biophysical properties, and sensitivity to neurotoxins. Four β subunits (β1–β4) and two splice variants (β1A, β1B) have been identified that modulate the subcellular distribution, cell surface expression, and functional properties of the α subunits. The purpose of this review is to provide a broad overview of β subunit expression and function in peripheral sensory neurons and examine their contributions to neuropathic pain.
Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
Marijke Stevens,Steve Peigneur,Jan Tytgat
Frontiers in Pharmacology , 2011, DOI: 10.3389/fphar.2011.00071
Abstract: Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called “channelopathies.” The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963. These concepts still form the basis for understanding the function of VGSCs. When VGSCs sense a sufficient change in membrane potential, they are activated and consequently generate a massive influx of sodium ions. Immediately after, channels will start to inactivate and currents decrease. In the inactivated state, channels stay refractory for new stimuli and they must return to the closed state before being susceptible to a new depolarization. On the other hand, studies with neurotoxins like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our today’s understanding of the structure and function of ion channels and of VGSCs specifically. Moreover, neurotoxins acting on ion channels turned out to be valuable lead compounds in the development of new drugs for the enormous range of diseases in which ion channels are involved. A recent example of a synthetic neurotoxin that made it to the market is ziconotide (Prialt?, Elan). The original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now FDA/EMA-approved for the management of severe chronic pain by blocking the N-type voltage-gated calcium channels in pain fibers. This review focuses on the current status of research on neurotoxins acting on VGSC, their contribution to further unravel the structure and function of VGSC and their potential as novel lead compounds in drug development.
Ciguatoxins: Cyclic Polyether Modulators of Voltage-gated Iion Channel Function
Graham M. Nicholson,Richard J. Lewis
Marine Drugs , 2006, DOI: 10.3390/md403082
Abstract: Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na+-dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera.
Marine Toxins That Target Voltage-gated Sodium Channels
Ahmed Al-Sabi,Jeff McArthur,Vitaly Ostroumov,Robert J. French
Marine Drugs , 2006, DOI: 10.3390/md403157
Abstract: Eukaryotic, voltage-gated sodium (NaV) channels are large membrane proteins which underlie generation and propagation of rapid electrical signals in nerve, muscle and heart. Nine different NaV receptor sites, for natural ligands and/or drugs, have been identified, based on functional analyses and site-directed mutagenesis. In the marine ecosystem, numerous toxins have evolved to disrupt NaV channel function, either by inhibition of current flow through the channels, or by modifying the activation and inactivation gating processes by which the channels open and close. These toxins function in their native environment as offensive or defensive weapons in prey capture or deterrence of predators. In composition, they range from organic molecules of varying size and complexity to peptides consisting of ~10-70 amino acids. We review the variety of known NaV-targeted marine toxins, outlining, where known, their sites of interaction with the channel protein and their functional effects. In a number of cases, these natural ligands have the potential applications as drugs in clinical settings, or as models for drug development.
Role of eslicarbazepine in the treatment of epilepsy in adult patients with partial-onset seizures
Martin E Brown, Rif S El-Mallakh
Therapeutics and Clinical Risk Management , 2010, DOI: http://dx.doi.org/10.2147/TCRM.S6382
Abstract: le of eslicarbazepine in the treatment of epilepsy in adult patients with partial-onset seizures Review (4296) Total Article Views Authors: Martin E Brown, Rif S El-Mallakh Published Date March 2010 Volume 2010:6 Pages 103 - 109 DOI: http://dx.doi.org/10.2147/TCRM.S6382 Martin E Brown, Rif S El-Mallakh 1Department of Neurology, 2Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky, USA Abstract: Eslicarbazepine is a new dibenzazepine antiepileptic agent. It is a high affinity antagonist of the voltage-gated sodium channel. It is closely related to both carbamazepine and oxcarbazepine. Eslicarbazepine has similar affinity to inactivated sodium channels (channels in just activated neurons) as carbamazepine, and greater efficacy in animal models of seizure than oxcarbazepine. In human placebo-controlled trials of a single daily dose of eslicarbazepine added to other anti-epileptic agents, significant seizure reductions occurred with 800 and 1200 mg daily, with nearly half of the patients experiencing a greater than 50% reduction in seizure frequency. Adverse events (AEs) occurred in over 50% of patients receiving therapeutic doses of eslicarbazepine (compared to 31.4%–44.7% of placebo-treated subjects), but were generally mild or moderate. Eight to 19.6% of eslicarbazepine treated patients discontinued due to AEs (compared to 3.9%–8.5% of placebo-treated subjects). In these patients receiving combination anticonvulsant therapy, the most common AEs were dizziness, nausea and vomiting, somnolence, and diplopia. Eslicarbazepine is an effective and reasonably well-tolerated adjunct in patients with suboptimal control of their partial seizures.
The non-synonymous SNP, R1150W, in SCN9A is not associated with chronic widespread pain susceptibility
Holliday Kate L,Thomson Wendy,Neogi Tuhina,Felson David T
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-72
Abstract: Background Mutations in SCN9A, encoding the alpha subunit of the voltage-gated sodium channel (Nav1.7), have caused severe pain disorders and congenital insensitivity to pain. The aim of this study was to validate the previously reported association between a common non-synonymous polymorphism (R1150W, rs6746030) in SCN9A and chronic widespread pain (CWP), in independent population-based cohorts. Findings Genotype data for rs6746030 was available in four population-based cohorts (EPIFUND, the European Male Ageing Study (EMAS), the Framingham study and the Dyne Steel DNA Bank of Ageing and Cognition). Pain was assessed using body manikins and CWP was scored using American College of Rheumatology (ACR) criteria in all cohorts, except the Framingham study which assessed widespread pain (WP) using ACR criteria on a joint pain homunculus. Controls were subjects who reported no pain. Logistic regression (additive genetic model) was used to test for association between rs6746030 and CWP compared to controls, adjusting for study centre in EMAS. Generalised estimating equation regression was used to test for association between rs6746030 and WP, whilst accounting for relatedness between subjects in the Framingham study. Genotype data for rs6746030 was available for 1071 CWP cases and 3212 controls. There was no significant association between CWP and rs6476030 in individual cohorts or when combined in a fixed-effects meta-analysis (Odds Ratio = 0.96 (95% confidence interval 0.82, 1.11) p = 0.567). Conclusions In contrast to a previous study, no association between a non-synonymous polymorphism in SCN9A and CWP was observed in multiple population-based cohorts.
Targeting voltage-gated sodium channels for treatment for chronic visceral pain
Fei-Hu Qi,You-Lang Zhou,Guang-Yin Xu
World Journal of Gastroenterology , 2011, DOI: 10.3748/wjg.v17.i19.2357
Abstract: Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability, and their abnormal activity is related to several pathological processes, including cardiac arrhythmias, epilepsy, neurodegenerative diseases, spasticity and chronic pain. In particular, chronic visceral pain, the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome, is a serious clinical problem that affects a high percentage of the world population. In spite of intense research efforts and after the dedicated decade of pain control and research, there are not many options to treat chronic pain conditions. However, there is a wealth of evidence emerging to give hope that a more refined approach may be achievable. By using electronic databases, available data on structural and functional properties of VGSCs in chronic pain, particularly functional gastrointestinal hypersensitivity, were reviewed. We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functional gastrointestinal disorders. We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases, and outline future developments that may extend the therapeutic use of compounds that target VGSCs. Overall, clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.
Correlation of the electrophysiological profiles and sodium channel transcripts of individual rat dorsal root ganglia neurons
Olivier Theriault,Mohamed Chahine
Frontiers in Cellular Neuroscience , 2014, DOI: 10.3389/fncel.2014.00285
Abstract: Voltage gated sodium channels (Na+ channels) play an important role in nociceptive transmission. They are intimately tied to the genesis and transmission of neuronal firing. Five different isoforms (Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) have been linked to nociceptive responses. A change in the biophysical properties of these channels or in their expression levels occurs in different pathological pain states. However, the precise involvement of the isoforms in the genesis and transmission of nociceptive responses is unknown. The aim of the present study was to investigate the synergy between the different populations Na+ channels that give individual neurons a unique electrophysical profile. We used the patch-clamp technique in the whole-cell configuration to record Na+ currents and action potentials from acutely dissociated small diameter DRG neurons (<30 μM) from adult rats. We also performed single cell qPCR on the same neurons. Our results revealed that there is a strong correlation between Na+ currents and mRNA transcripts in individual neurons. A cluster analysis showed that subgroups formed by Na+ channel transcripts by mRNA quantification have different biophysical properties. In addition, the firing frequency of the neurons was not affected by the relative populations of Na+ channel. The synergy between populations of Na+ channel in individual small diameter DRG neurons gives each neuron a unique electrophysiological profile. The Na+ channel remodeling that occurs in different pathological pain states may be responsible for the sensitization of the neurons.
Multiple voltage-gated sodium channel α subunits expressed in adult rat ventricular myocytes

- , 2017, DOI: 10.7652/jdyxb201706004
Abstract: 摘要:目的 观察成年大鼠心室肌细胞上电压门控钠通道不同亚型的表达情况。方法 采用酶解消化法分离成年大鼠心室肌细胞,利用免疫荧光染色结合激光共聚焦技术检测心室肌细胞钠通道α亚型Nav1.1、Nav1.2、Nav1.3、Nav1.5、Nav1.6、Nav1.7的表达及分布情况,采用全细胞膜片钳技术记录心室肌细胞钠电流。结果 成年大鼠心室肌细胞除表达心脏型钠通道亚型Nav1.5之外,还表达神经型钠通道亚型Nav1.1、Nav1.6和Nav1.7,不表达Nav1.2和Nav1.3。Nav1.5分布于横小管周围,Nav1.1和Nav1.7亦呈点状分布于横小管区域。Nav1.6表达稍弱,沿心室肌细胞长轴纵向分布,闰盘处未见钠通道各α亚型的表达。膜片钳结果显示成年大鼠心室肌细胞表达快钠电流(INa,T)及晚钠电流(INa,L)。结论 成年大鼠心室肌细胞表达心脏型钠通道亚型(Nav1.5)和多种神经型钠通道亚型(Nav1.1、Nav1.6和Nav1.7),这可能有助于维持心肌细胞的正常电生理活动。
ABSTRACT: Objective To observe the expressions of voltage-gated sodium channel (NaCh) α subunits in adult rat ventricular myocytes. Methods Single ventricular myocytes were isolated from adult rat heart. Expressions of various α subunits (Nav1.1, Nav1.2, Nav1.3, Nav1.5, Nav1.6 and Nav1.7) of NaCh in the ventricular myocytes were detected by immunocytochemistry staining. Sodium current was recorded by whole-cell patch clamp method. Results The neuronal subunits Nav1.1, Nav1.6 and Nav1.7 as well as the cardiac subunit Nav1.5 of NaCh were expressed in adult rat ventricular myocytes. Nav1.1, Nav1.5 and Nav1.7 were distributed along the cell membrane of the ventricular myocytes and around the transverse tubule; Nav1.6 was labeled along the cell membrane by lengthways. All these subunits were not colocalized with Cx43 at the intercalated disc. Both transient sodium current (INa,T) and late sodium current (INa,L) were recorded from adult rat ventricular myocytes. Conclusion Various neuronal subunits (Nav1.1, Nav1.6 and Nav1.7) as well as cardiac subunit (Nav1.5) of NaCh were expressed in adult rat ventricular myocytes, which is important for normal function of INa,T and INa,L
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