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‣ ABNORMAL EXPRESSION OF VOLTAGE-GATED SODIUM CHANNELS Nav1.7, Nav1.3 AND Nav1.8 IN TRIGEMINAL NEURALGIA

SIQUEIRA, S. R. D. T.; ALVES, B.; MALPARTIDA, H. M. G.; TEIXEIRA, M. J.; SIQUEIRA, J. T. T.
Fonte: PERGAMON-ELSEVIER SCIENCE LTD Publicador: PERGAMON-ELSEVIER SCIENCE LTD
Tipo: Artigo de Revista Científica
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Voltage-gated sodium channels have been implicated in acute and chronic neuropathic pain. Among subtypes, Nav1.7 single mutations can cause congenital indifference to pain or chronic neuropathic pain syndromes, including paroxysmal ones. This channel is co-expressed with Nav1.8, which sustains the initial action potential; Nav1.3 is an embrionary channel which is expressed in neurons after injury, as in neuropathic conditions. Few studies are focused on the expression of these molecules in human tissues having chronic pain. Trigeminal neuralgia (TN) is an idiopathic paroxysmal pain treated with sodium channel blockers. The aim of this study was to investigate the expression of Nav1.3, Nav1.7 and Nav1.8 by RT-PCR in patients with TN, compared to controls. The gingival tissue was removed from the correspondent trigeminal area affected. We found that Nav1.7 was downregulated in TN (P=0.017) and Nav1.3 was upregulated in these patients (P=0.043). We propose a physiopathological mechanism for these findings. Besides vascular compression of TN, this disease might be also a channelopathy. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

‣ Calcium Block of Single Sodium Channels: Role of a Pore-Lining Aromatic Residue

Santarelli, Vincent P.; Eastwood, Amy L.; Dougherty, Dennis A.; Ahern, Christopher A.; Horn, Richard
Fonte: Biophysical Society Publicador: Biophysical Society
Tipo: Artigo de Revista Científica
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Extracellular Ca2+ ions cause a rapid block of voltage-gated sodium channels, manifest as an apparent reduction of the amplitude of single-channel currents. We examined the influence of residue Tyr-401 in the isoform rNaV1.4 on both single-channel conductance and Ca2+ block. An aromatic residue at this position in the outer mouth of the pore plays a critical role in high-affinity block by the guanidinium toxin tetrodotoxin, primarily due to an electrostatic attraction between the cationic blocker and the system of π electrons on the aromatic face. We tested whether a similar attraction between small metal cations (Na+ and Ca2+) and this residue would enhance single-channel conductance or pore block, using a series of fluorinated derivatives of phenylalanine at this position. Our results show a monotonic decrease in Ca2+ block as the aromatic ring is increasingly fluorinated, a result in accord with a cation-π interaction between Ca2+ and the aromatic ring. This occurred without a change of single-channel conductance, consistent with a greater electrostatic effect of the π system on divalent than on monovalent cations. High-level quantum mechanical calculations show that Ca2+ ions likely do not bind directly to the aromatic ring because of the substantial energetic penalty of dehydrating a Ca2+ ion. However...

‣ Functional Expression of Drosophila para Sodium Channels : Modulation by the Membrane Protein TipE and Toxin Pharmacology

Warmke, Jeffrey W.; Reenan, Robert A.G.; Wang, Peiyi; Qian, Su; Arena, Joseph P.; Wang, Jixin; Wunderler, Denise; Liu, Ken; Kaczorowski, Gregory J.; Ploeg, Lex H.T. Van der; Ganetzky, Barry; Cohen, Charles J.
Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/08/1997 Português
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The Drosophila para sodium channel α subunit was expressed in Xenopus oocytes alone and in combination with tipE, a putative Drosophila sodium channel accessory subunit. Coexpression of tipE with para results in elevated levels of sodium currents and accelerated current decay. Para/TipE sodium channels have biophysical and pharmacological properties similar to those of native channels. However, the pharmacology of these channels differs from that of vertebrate sodium channels: (a) toxin II from Anemonia sulcata, which slows inactivation, binds to Para and some mammalian sodium channels with similar affinity (Kd ≅ 10 nM), but this toxin causes a 100-fold greater decrease in the rate of inactivation of Para/TipE than of mammalian channels; (b) Para sodium channels are >10-fold more sensitive to block by tetrodotoxin; and (c) modification by the pyrethroid insecticide permethrin is >100-fold more potent for Para than for rat brain type IIA sodium channels. Our results suggest that the selective toxicity of pyrethroid insecticides is due at least in part to the greater affinity of pyrethroids for insect sodium channels than for mammalian sodium channels.

‣ Trans-Channel Interactions in Batrachotoxin-Modified Rat Skeletal Muscle Sodium Channels: Kinetic Analysis of Mutual Inhibition between μ-Conotoxin GIIIA Derivatives and Amine Blockers

Ma, Quanli; Pavlov, Evgeny; Britvina, Tatiana; Zamponi, Gerald W.; French, Robert J.
Fonte: The Biophysical Society Publicador: The Biophysical Society
Tipo: Artigo de Revista Científica
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R13X derivatives of μ-conotoxin GIIIA bind externally to single sodium channels and block current incompletely with mean “blocked” durations of several seconds. We studied interactions between two classes of blockers (μ-conotoxins and amines) by steady state, kinetic analysis of block of BTX-modified Na channels in planar bilayers. The amines cause all-or-none block at a site internal to the selectivity filter. TPrA and DEA block single Na channels with very different kinetics. TPrA induces discrete, all-or-none, blocked events (mean blocked durations, ∼100 ms), whereas DEA produces a concentration-dependent reduction of the apparent single channel amplitude (“fast” block). These distinct modes of action allow simultaneous evaluation of block by TPrA and DEA, showing a classical, competitive interaction between them. The apparent affinity of TPrA decreases with increasing [DEA], based on a decrease in the association rate for TPrA. When an R13X μ-conotoxin derivative and one of the amines are applied simultaneously on opposite sides of the membrane, a mutually inhibitory interaction is observed. Dissociation constants, at +50 mV, for TPrA (∼4 mM) and DEA (∼30 mM) increase by ∼20%–50% when R13E (nominal net charge...

‣ Analysis of the action of lidocaine on insect sodium channels

Song, Weizhong; Silver, Kristopher S.; Du, Yuzhe; Liu, Zhiqi; Dong, Ke
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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A new class of sodium channel blocker insecticides (SCBIs), which include indoxacarb, its active metabolite, DCJW, and metaflumizone, preferably block inactivated states of both insect and mammalian sodium channels in a manner similar to that by which local anesthetic (LA) drugs block mammalian sodium channels. A recent study showed that two residues in the cockroach sodium channel, F1817 and Y1824, corresponding to two key LA-interacting residues identified in mammalian sodium channels are not important for the action of SCBIs on insect sodium channels, suggesting unique interactions of SCBIs with insect sodium channels. However, the mechanism of action of LAs on insect sodium channels has not been investigated. In this study, we examined the effects of lidocaine on a cockroach sodium channel variant, BgNav1-1a, and determined whether F1817 and Y1824 are also critical for the action of LAs on insect sodium channels. Lidocaine blocked BgNav1-1a channels in the resting state with potency similar to that observed in mammalian sodium channels. Lidocaine also stabilized both fast-inactivated and slow-inactivated states of BgNav1-1a channels, and caused a limited degree of use- and frequency-dependent block, major characteristics of LA action on mammalian sodium channels. Alanine substitutions of F1817 and Y1824 reduced the sensitivity of the BgNav1-1a channel to the use-dependent block by lidocaine...

‣ Integral voltage-gated sodium channels: production, characterisation and investigation into oligomeric state detergent dependence

McCarthy, Marguerita
Fonte: University of Limerick Publicador: University of Limerick
Tipo: info:eu-repo/semantics/doctoralThesis; all_ul_research; ul_published_reviewed; ul_theses_dissertations
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peer-reviewed; Voltage-gated sodium channels underlie membrane potentials and electrical excitability in eukaryotes. Malfunctioning sodium channels give rise to conditions such as epilepsy, sensitivity to pain and cardiac arrhythmia. Structural and functional studies of voltage-gated sodium channels are therefore required in order to describe their mechanisms of action and subsequently develop specific drugs for treatments. Research into bacterial voltage-gated sodium channels started in 2001 when Ren et al. (2001) discovered their presence in bacteria and has escalated since the publication of the first structure in July 2011 with subsequent elucidation of two further bacterial voltage-gated sodium channel structures. In order to fully understand the mechanism of their eukaryotic counterparts there is a demand for further bacterial structures from a wide variety of species. One of the bottlenecks in amassing a database of bacterial structures is the protein behaviour during purification process leading to tetramer formation required for crystal formation. This study started in 2010 with the production and crystallisation of voltage-gated sodium channels from Pseudoalteromonas haloplanktis (NavPh) and Roseobacter litoralis (NavRl) and addressed the lack of procedures for preparation of tetramers. An investigation into the dependence of oligomeric state on detergents was performed. Patterns of behaviour were identified and preparation procedures were suggested. Both monomeric and tetrameric species of the selected targets were produced in milligram quantities...

‣ Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2

Fotia, A.; Ekberg, J.; Adams, D.; Cook, D.; Poronnik, P.; Kumar, S.
Fonte: Amer Soc Biochemistry Molecular Biology Inc Publicador: Amer Soc Biochemistry Molecular Biology Inc
Tipo: Artigo de Revista Científica
Publicado em //2004 Português
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Nedd4 and Nedd4-2 are ubiquitin-protein ligases known to regulate a number of membrane proteins including receptors and ion transporters. Regulation of the epithelial Na(+) channel by Nedd4 and Nedd4-2 is mediated via interactions between the PY motifs of the epithelial sodium channel subunits and the Nedd4/Nedd4-2 WW domains. This example serves as a model for the regulation of other PY motif-containing ion channels by Nedd4 and Nedd4-2. We found that the carboxyl termini of the six voltage-gated Na(+) (Na(v)) channels contain typical PY motifs (PPXY), and a further Na(v) contains a PY motif variant (LPXY). Not only did we demonstrate by Far-Western analysis that Nedd4 and Nedd4-2 interact with the PY motif-containing Na(v) channels, but we also showed that these channels have conserved WW domain binding specificity. We further showed that the carboxyl termini fusion proteins of one central nervous system and one peripheral nervous system-derived Na(+) channel (Na(v)1.2 and Na(v)1.7, respectively) are readily ubiquitinated by Nedd4-2. In Xenopus oocytes, Nedd4-2 strongly inhibited the activities of all three Na(v)s (Na(v)1.2, Na(v)1.7, and Na(v)1.8) tested. Interestingly, Nedd4 suppressed the activity of Na(v)1.2 and Na(v)1.7 but was a poor inhibitor of Na(v)1.8. Our results provide evidence that Nedd4 and Nedd4-2 are likely to be key regulators of specific neuronal Na(v) channels in vivo.

‣ Nedd4-2 (NEDD4L) controls intracellular Na⁺ -mediated activity of voltage-gated sodium channels in primary cortical neurons; Nedd4-2 (NEDD4L) controls intracellular Na(+) -mediated activity of voltage-gated sodium channels in primary cortical neurons

Ekberg, J.; Boase, N.; Rychkov, G.; Manning, J.; Poronnik, P.; Kumar, S.
Fonte: Portland Press Publicador: Portland Press
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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Nedd4-2, a HECT (homologous with E6-associated protein C-terminus)-type ubiquitin protein ligase, has been implicated in regulating several ion channels, including Navs (voltage-gated sodium channels). In Xenopus oocytes Nedd4-2 strongly inhibits the activity of multiple Navs. However, the conditions under which Nedd4-2 mediates native Nav regulation remain uncharacterized. Using Nedd4-2-deficient mice, we demonstrate in the present study that in foetal cortical neurons Nedd4-2 regulates Navs specifically in response to elevated intracellular Na+, but does not affect steady-state Nav activity. In dorsal root ganglia neurons from the same mice, however, Nedd4-2 does not control Nav activities. The results of the present study provide the first physiological evidence for an essential function of Nedd4-2 in regulating Navs in the central nervous system.; Jenny A. Ekberg, Natasha A. Boase, Grigori Rychkov, Jantina Manning, Philip Poronnik and Sharad Kumar

‣ mRNA Variants of a Neuronal Sodium Channel in Rat Cardiac Myocytes

Lafreniere, Gina
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
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Death due to ischemic heart disease (IHD) is the result of cardiac arrhythmias and loss of cardiac pump function. One of the putative underlying mechanisms is impaired inactivation of voltage-gated sodium channels (VGSC), resulting in small persistent sodium currents. Nine VGSC (NaV1.1-NaV1.9) have been cloned and functionally expressed. Electrophysiological/pharmacological evidence suggests that “neuronal” isoform(s) exist in cardiomyocytes along with the cardiac-dominant NaV1.5. Given that persistent currents have been shown to be fundamental to the function of neuronal isoforms and that pharmacological evidence suggests that neuronal VGSC underlie increases in persistent currents during ischemic events, we hypothesized that neuronal VGSC are present in cardiomyocytes. Specifically, the purpose of this study was to demonstrate that the neuronal VGSC NaV1.1 exists in rat right ventricular myocytes. The full-length NaV1.1 coding sequence was cloned in overlapping segments. Through sequencing, we identified one amino acid difference from a published brain sequence (c.2935A>G) and four deletion variants (c.[del266_473], c.[del2012_2044], c.[del4004_4258], and c.[del4003_4284]). The deletion variants were not present in all sequenced amplicons. Deletions at the first and the third deletion sites were of particular interest as these involved regions of conserved sequence...

‣ Characterization of selectivity and pharmacophores of type 1 sea anemone toxins by screening seven Na-v sodium channel isoforms

Zaharenko, Andre Junqueira; Schiavon, Emanuele; Ferreira, Wilson Alves, Jr.; Lecchi, Marzia; de Freitas, Jose Carlos; Richardson, Michael; Wanke, Enzo
Fonte: ELSEVIER SCIENCE INC; NEW YORK Publicador: ELSEVIER SCIENCE INC; NEW YORK
Tipo: Artigo de Revista Científica
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During their evolution, animals have developed a set of cysteine-rich peptides capable of binding various extracellular sites of voltage-gated sodium channels (VGSC). Sea anemone toxins that target VGSCs delay their inactivation process, but little is known about their selectivities. Here we report the investigation of three native type 1 toxins (CGTX-II, delta-AITX-Bcg1a and delta-AITX-Bcg1b) purified from the venom of Bunodosoma cangicum. Both delta-AITX-Bcg1a and delta-AITX-Bcg1b toxins were fully sequenced. The three peptides were evaluated by patch-clamp technique among Nav1.1-1.7 isoforms expressed in mammalian cell lines, and their preferential targets are Na(v)1.5 > 1.6 > 1.1. We also evaluated the role of some supposedly critical residues in the toxins which would interact with the channels, and observed that some substitutions are not critical as expected. In addition, CGTX-II and delta-AITX-Bcg1a evoke different shifts in activation/inactivation Boltzmann curves in Nav1.1 and 1.6. Moreover, our results suggest that the interaction region between toxins and VGSCs is not restricted to the supposed site 3 (S3-54 linker of domain IV), and this may be a consequence of distinct surface of contact of each peptide vs. targeted channel. Our data suggest that the contact surfaces of each peptide may be related to their surface charges...

‣ Trans-Channel Interactions in Batrachotoxin-Modified Skeletal Muscle Sodium Channels: Voltage-Dependent Block by Cytoplasmic Amines, and the Influence of μ-Conotoxin GIIIA Derivatives and Permeant Ions

Pavlov, Evgeny; Britvina, Tatiana; McArthur, Jeff R.; Ma, Quanli; Sierralta, Iván; Zamponi, Gerald W.; French, Robert J.
Fonte: The Biophysical Society Publicador: The Biophysical Society
Tipo: Artigo de Revista Científica
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External μ-conotoxins and internal amine blockers inhibit each other's block of voltage-gated sodium channels. We explore the basis of this interaction by measuring the shifts in voltage-dependence of channel inhibition by internal amines induced by two μ-conotoxin derivatives with different charge distributions and net charges. Charge changes on the toxin were made at residue 13, which is thought to penetrate most deeply into the channel, making it likely to have the strongest individual interaction with an internal charged ligand. When an R13Q or R13E molecule was bound to the channel, the voltage dependence of diethylammonium (DEA)-block shifted toward more depolarized potentials (23 mV for R13Q, and 16 mV for R13E). An electrostatic model of the repulsion between DEA and the toxin simulated these data, with a distance between residue 13 of the μ-conotoxin and the DEA-binding site of ∼15 Å. Surprisingly, for tetrapropylammonium, the shifts were only 9 mV for R13Q, and 7 mV for R13E. The smaller shifts associated with R13E, the toxin with a smaller net charge, are generally consistent with an electrostatic interaction. However, the smaller shifts observed for tetrapropylammonium than for DEA suggest that other factors must be involved. Two observations indicate that the coupling of permeant ion occupancy of the channel to blocker binding may contribute to the overall amine-toxin interaction: 1)...

‣ Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes

Laedermann, Cedric J.; Abriel, Hugues; Decosterd, Isabelle
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
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In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating...

‣ Structural analysis of Tityus serrulatus Ts1 neurotoxin at atomic resolution: insights into interactions with Na+ channels

Pinheiro, C. B.; Marangoni, S.; Toyama, M. H.; Polikarpov, I.
Fonte: International Union of Crystallography Publicador: International Union of Crystallography
Tipo: Artículo Formato: 13824 bytes; application/vnd.ms-excel
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11 pages, 7 figures, 2 tables.; The structure of the Ts1 toxin from the Brazilian scorpion Tityus serrulatus was investigated at atomic resolution using X-ray crystallography. Several positively charged niches exist on the Ts1 molecular surface, two of which were found to coordinate phosphate ions present in the crystallization solution. One phosphate ion is bound to the conserved basic Lys1 residue at the Ts1 N-terminus and to residue Asn49. The second ion was found to be caged by residues Lys12, Trp54 and Arg56. Lys12 and Tyr/Trp54 residues are strictly conserved in all classical scorpion [beta]-neurotoxins. The cavity formed by these residues may represent a special scaffold required for interaction between [beta]-neurotoxins and sodium channels. The charge distribution on the Ts1 surface and the results of earlier chemical modification studies and side-directed mutagenesis experiments strongly indicate that the phosphate-ion positions mark plausible binding sites to the Na+ channel. The existence of two distinct binding sites on the Ts1 molecular surface provides an explanation for the competition between Ts1, depressant (LqhIT2) and excitatory (AaHIT) neurotoxins.; This work was supported by the FAPESP (FundacËaÄo de Amparo aÁ Pesquisa do Estado de SaÄo Paulo) grants 99/08042-5 and 99/03387-4.We thank Professor Oussama Hassani for kindly providing us with the coordinates of the Ts1 neurotoxin obtained by comparative modelling and the LNLS personnel for giving us access to the synchrotron-facility infrastructure.; Peer reviewed

‣ Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions

Tse, Gary; Yeo, Jie Ming
Fonte: Elsevier Publicador: Elsevier
Tipo: Article; published version
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This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ijcha.2015.10.003; Ventricular arrhythmias arise from disruptions in the normal orderly sequence of electrical activation and recovery of the heart. They can be categorized into disorders affecting predominantly cellular depolarization or repolarization, or those involving action potential (AP) conduction. This article briefly discusses the factors causing conduction abnormalities in the form of unidirectional conduction block and reduced conduction velocity (CV). It then examines the roles that sodium channels and gap junctions play in AP conduction. Finally, it synthesizes experimental results to illustrate molecular mechanisms of how abnormalities in these proteins contribute to such conduction abnormalities and hence ventricular arrhythmogenesis, in acquired pathologies such as acute ischaemia and heart failure, as well as inherited arrhythmic syndromes.; GT received a BBSRC Doctoral CASE Studentship at the Department of Biochemistry, University of Cambridge, in conjunction with Xention Discovery, for his Ph.D. studies. This manuscript is based, in part, on the doctoral thesis of GT. GT thanks Dr. Antony Workman of University of Glasgow...

‣ Oxygen-sensing persistent sodium channels in rat hippocampus

Hammarstrom, Anna; Gage, Peter
Fonte: Cambridge University Press Publicador: Cambridge University Press
Tipo: Artigo de Revista Científica
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1. Persistent sodium channel activity was recorded before and during hypoxia from cell-attached and inside-out patches obtained from cultured hippocampal neurons at a pipette potential (V(p)) of +30 mV. Average mean current (I') of these channels was very low under normoxic conditions and was similar in cell-attached and excised inside-out patches (-0.018 ± 0.010 and -0.025 ± 0.008 pA, respectively, n = 24). 2. Hypoxia increased the activity of persistent sodium channels in 10 cell-attached patches (I' increased from -0.026 ± 0.016 pA in control to -0.156 ± 0.034 pA during hypoxia, n = 4, P = 0.013). The increased persistent sodium channel activity was most prominent at a V(p) between +70 and +30 mV (membrane potential, V(m) = -70 to -30 mV) and could be blocked by lidocaine, TTX or R56865 (n = 5). Sodium cyanide (NaCN, 5 mM; 0.5-5 min) increased persistent sodium channel activity in cell-attached patches (n = 3) in a similar manner. 3. Hypoxia also increased sodium channel activity in inside-out patches from hippocampal neurons. Within 2-4 min of exposure to hypoxia, I' had increased 9-fold to -0.18 ± 0.04 pA (n = 21, P = 0.001). Sodium channel activity increased further with longer exposures to hypoxia. 4. The hypoxia-induced sodium channel activity in inside-out patches could be inhibited by exposure to 10-100 μM lidocaine applied via the bath solution (I' = -0.03 ± 0.01 pA...

‣ Solution Structure of mu-Conotoxin PIIIA, a Preferential Inhibitor of Persistent Tetrodotoxin-sensitive Sodium Channels

Nielsen, Katherine; Watson, Michael; Adams, David; Hammarstrom, Anna; Gage, Peter; Hill, James O; Craik, David J; Thomas, Linda; Adams, Denise; Alewood, Paul F; Lewis, Richard L
Fonte: American Society for Biochemistry and Molecular Biology Inc Publicador: American Society for Biochemistry and Molecular Biology Inc
Tipo: Artigo de Revista Científica
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μ-Conotoxins are peptide inhibitors of voltage-sensitive sodium channels (VSSCs). Synthetic forms of μ-conotoxins PIIIA and PIIIA-(2-22) were found to inhibit tetrodotoxin (TTX)-sensitive VSSC current but had little effect on TTX-resistant VSSC current

‣ Hypoxia and persistent sodium current

Hammarstrom, Anna; Gage, Peter
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
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During prolonged depolarization of excitable cells, some voltage-activated, tetrodotoxin-sensitive sodium channels are resistant to inactivation and can continue to open for long periods of time, generating a "persistent" sodium current (INaP). The amplitude of INaP is small [generally less than 1% of the peak amplitude of the transient sodium current (INaT)], activates at potentials close to the resting membrane potential, and is more sensitive to Na channel blocking drugs than INaT. It is thought that persistent Na channels are generated by a change in gating of transient Na channels, possibly because of a change in phosphorylation or protein structure, e.g. loss of the inactivation gate. Drugs that block Na channels can prevent the increase in [Ca2+]i in cardiac cells during hypoxia. Hypoxia increases the amplitude of INaP. Paradoxically, NO causes a similar increase in INaP and the effects of both can be inhibited by reducing agents such as dithiothreitol and reduced glutathione. It is proposed that an increased inflow of Na+ during hypoxia increases [Na+]i, which in turn reverses the Na/Ca exchanger so that [Ca2+]i rises. An increase in INaP and [Ca2+]i could cause arrhythmias and irreversible cell damage.

‣ Voltage-activated sodium channels amplify inhibition in neocortical pyramidal neurons

Stuart, Gregory J
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Inhibitory postsynaptic potentials (IPSPs) in neocortical pyramidal neurons are increased in duration and amplitude at depolarized membrane potentials. This effect was not due to changes in the time course of the underlying synaptic current. The role of postsynaptic voltage-activated channels was investigated by mimicking the voltage change that occurs during an IPSP with current injections. The peak and integral of these 'simulated' IPSPs increased during depolarization of the membrane potential in a tetrodotoxin-sensitive manner. This amplification presumably occurs as the hyperpolarization associated with IPSPs turns off sodium channels that are tonically active at depolarized membrane potentials. IPSP amplification increased the ability of IPSPs to inhibit action potential firing and promoted IPSP-induced action potential synchronization.

‣ A Model of Sodium Channels

Vora, Taira; Corry, Ben; Chung, Shin-Ho
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
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We have explored the permeation and blockage of ions in sodium channels, relating the channel structure to function using electrostatic profiles and Brownian dynamics simulations. The model used resembles the KcsA potassium channel with an added external

‣ Nav1.5 cardiac sodium channels, regulation and clinical implications

León-Ariza,Henry Humberto; Valenzuela-Faccini,Natalia; Rojas-Ortega,Ariana Carolina; Botero-Rosas,Daniel Alfonso
Fonte: Revista de la Facultad de Medicina Publicador: Revista de la Facultad de Medicina
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/2014 Português
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Voltage-gated sodium channels constitute a group of membrane proteins widely distributed thought the body. In the heart, there are at least six different isoforms, being the Nav1.5 the most abundant. The channel is composed of an α subunit that is formed by four domains of six segments each, and four much smaller β subunits that provide stability and integrate other channels into the α subunit. The function of the Nav1.5 channel is modulated by intracellular cytoskeleton proteins, extracellular proteins, calcium concentration, free radicals, and medications, among other things. The study of the channel and its alterations has grown thanks to its association with pathogenic conditions such as Long QT syndrome, Brugada syndrome, atrial fibrillation, arrhythmogenic ventricular dysplasia and complications during ischemic processes.