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Shellfish Toxins Targeting Voltage-Gated Sodium Channels  [PDF]
Fan Zhang,Xunxun Xu,Tingting Li,Zhonghua Liu
Marine Drugs , 2013, DOI: 10.3390/md11124698
Abstract: Voltage-gated sodium channels (VGSCs) play a central role in the generation and propagation of action potentials in excitable neurons and other cells and are targeted by commonly used local anesthetics, antiarrhythmics, and anticonvulsants. They are also common targets of neurotoxins including shellfish toxins. Shellfish toxins are a variety of toxic secondary metabolites produced by prokaryotic cyanobacteria and eukaryotic dinoflagellates in both marine and fresh water systems, which can accumulate in marine animals via the food chain. Consumption of shellfish toxin-contaminated seafood may result in potentially fatal human shellfish poisoning. This article provides an overview of the structure, bioactivity, and pharmacology of shellfish toxins that act on VGSCs, along with a brief discussion on their pharmaceutical potential for pain management.
Conotoxins Targeting Neuronal Voltage-Gated Sodium Channel Subtypes: Potential Analgesics?  [PDF]
Oliver Knapp,Jeffrey R. McArthur,David J. Adams
Toxins , 2012, DOI: 10.3390/toxins4111236
Abstract: Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic of inflammatory and neuropathic pain states. Therefore, VGSC modulators could be used in prospective analgesic compounds. VGSCs have specific binding sites for four conotoxin families: μ-, μO-, δ- and ?-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined areas or domains. To date, only the μ- and μO-family exhibit analgesic properties in animal pain models. This review will focus on conotoxins from the μ- and μO-families that act on neuronal VGSCs. Examples of how these conotoxins target various pharmacologically important neuronal ion channels, as well as potential problems with the development of drugs from conotoxins, will be discussed.
Overview of the voltage-gated sodium channel family
Frank H Yu, William A Catterall
Genome Biology , 2003, DOI: 10.1186/gb-2003-4-3-207
Abstract: Voltage-gated sodium channels play an essential role in the initiation and propagation of action potentials in neurons and other electrically excitable cells such as myocytes and endocrine cells [1,2]. When the cell membrane is depolarized by a few millivolts, sodium channels activate and inactivate within milliseconds. Influx of sodium ions through the integral membrane proteins comprising the channel depolarizes the membrane further and initiates the rising phase of the action potential. The voltage-gated sodium channel is a large, multimeric complex, composed of an α subunit and one or more smaller β subunits [3]. The ion-conducting aqueous pore is contained entirely within the α subunit, and the essential elements of sodium-channel function - channel opening, ion selectivity and rapid inactivation - can be demonstrated when α subunits are expressed alone in heterologous cells. Coexpression of the β subunit is required for full reconstitution of the properties of native sodium channels, as these auxiliary subunits modify the kinetics and voltage-dependence of the gating (that is, opening and closing) of the channel. Although different sodium channels have broadly similar functional characteristics, small differences in properties do distinguish different isoforms and contribute to their specialized functional roles in mammalian physiology and pharmacology. Sodium channels that are not voltage-gated also exist in biology; the epithelial sodium channels (EnaC) of the EnaC/degenerin (DEG) gene family mediate sodium transport in epithelia and other cell types and are structurally unrelated to the voltage-gated sodium channels. We use the term 'sodium channel' here to mean 'voltage-gated sodium channel'.Sodium-channel proteins in the mammalian brain are composed of a complex of a 260 kDa α subunit in association with one or more auxiliary β subunits (β1, β2 and/or β3) of 33-36 kDa [3] (Figure 1). Nine α subunits (Nav1.1-Nav1.9) have been functionally characterized, an
Excitability Constraints on Voltage-Gated Sodium Channels  [PDF]
Elaine Angelino,Michael P Brenner
PLOS Computational Biology , 2007, DOI: 10.1371/journal.pcbi.0030177
Abstract: We study how functional constraints bound and shape evolution through an analysis of mammalian voltage-gated sodium channels. The primary function of sodium channels is to allow the propagation of action potentials. Since Hodgkin and Huxley, mathematical models have suggested that sodium channel properties need to be tightly constrained for an action potential to propagate. There are nine mammalian genes encoding voltage-gated sodium channels, many of which are more than ≈90% identical by sequence. This sequence similarity presumably corresponds to similarity of function, consistent with the idea that these properties must be tightly constrained. However, the multiplicity of genes encoding sodium channels raises the question: why are there so many? We demonstrate that the simplest theoretical constraints bounding sodium channel diversity—the requirements of membrane excitability and the uniqueness of the resting potential—act directly on constraining sodium channel properties. We compare the predicted constraints with functional data on mammalian sodium channel properties collected from the literature, including 172 different sets of measurements from 40 publications, wild-type and mutant, under a variety of conditions. The data from all channel types, including mutants, obeys the excitability constraint; on the other hand, channels expressed in muscle tend to obey the constraint of a unique resting potential, while channels expressed in neuronal tissue do not. The excitability properties alone distinguish the nine sodium channels into four different groups that are consistent with phylogenetic analysis. Our calculations suggest interpretations for the functional differences between these groups.
Molecular and functional characterization of voltage-gated sodium channels in human sperm
Francisco M Pinto, Cristina G Ravina, Manuel Fernández-Sánchez, Manuel Gallardo-Castro, Antonio Cejudo-Román, Luz Candenas
Reproductive Biology and Endocrinology , 2009, DOI: 10.1186/1477-7827-7-71
Abstract: Freshly ejaculated semen was collected from thirty normozoospermic human donors, with each donor supplying 2 different samples. Reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence techniques were used to detect the mRNAs and proteins of interest. Sperm motility was measured by a computer-assisted sperm analysis system (CASA). Cytosolic free calcium was determined by fluorimetry in cells loaded with the fluorescent calcium indicator Fura-2.The mRNAs that encode the different Nav alpha subunits (Nav1.1-1.9) were all expressed in capacitated human spermatozoa. The mRNAs of the auxiliary subunits beta1, beta3 and beta4 were also present. Immunofluorescence studies showed that, with the exception of Nav1.1 and Nav1.3, the Nav channel proteins were present in sperm cells and show specific and different sites of localization. Veratridine, a voltage-gated sodium channel activator, caused time- and concentration-dependent increases in progressive sperm motility. In sperm suspensions loaded with Fura-2, veratridine did not modify intracellular free calcium levels.This research shows the presence of voltage-gated sodium channels in human sperm and supports a role for these channels in the regulation of mature sperm function.Voltage-gated sodium channels (VGSCs) play an essential role in the generation of the rapid depolarization during the initial phase of the action potential in excitable cells [1,2]. These complex membrane proteins are composed of an α and one or more auxiliary β subunits [2,3]. The α subunits are large proteins with a high degree of amino acid sequence identity; they contain an ion-conducting aqueous pore and can function without the β subunit as a Na+ channel [2-4]. Nine different voltage-dependent Na+ channel α subunits have been cloned in mammals, each of which is encoded by a different gene [5]. They can be further characterized by their sensitivity to the highly selective blocker tetrodotoxin (TTX). The TTX-sensitive α subun
Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels  [PDF]
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.
Voltage-gated sodium channels in taste bud cells
Na Gao, Min Lu, Fernando Echeverri, Bianca Laita, Dalia Kalabat, Mark E Williams, Peter Hevezi, Albert Zlotnik, Bryan D Moyer
BMC Neuroscience , 2009, DOI: 10.1186/1471-2202-10-20
Abstract: We describe the molecular and histological expression profiles of cation channels involved in electrical signal transmission from apical to basolateral membrane domains. TRPM5 was positioned immediately beneath tight junctions to receive calcium signals originating from sweet, bitter, and umami receptor activation, while PKD2L1 was positioned at the taste pore. Using mouse taste bud and lingual epithelial cells collected by laser capture microdissection, SCN2A, SCN3A, and SCN9A voltage-gated sodium channel transcripts were expressed in taste tissue. SCN2A, SCN3A, and SCN9A were expressed beneath tight junctions in subsets of taste cells. SCN3A and SCN9A were expressed in TRPM5 cells, while SCN2A was expressed in TRPM5 and PKD2L1 cells. HCN4, a gene previously implicated in sour taste, was expressed in PKD2L1 cells and localized to cell processes beneath the taste pore.SCN2A, SCN3A and SCN9A voltage-gated sodium channels are positioned to sense initial depolarizing signals stemming from taste receptor activation and initiate taste cell action potentials. SCN2A, SCN3A and SCN9A gene products likely account for the tetrodotoxin-sensitive sodium currents in taste receptor cells.Taste buds house specialized neuroepithelial cells that sense and transmit information regarding the composition of food [1]. These taste cells express receptors for sweet, bitter, umami (the savory taste of glutamate), sour and salty tastants in apical microvilli facing the saliva [2,3]. Following taste receptor activation, taste cells depolarize and fire action potentials resulting in the release of neurotransmitters to nerve fibers innervating basolateral membranes [4,5]. Segregation of taste receptors at the taste pore from the machinery involved in transmitting signals to nerve fibers is mediated by tight junctions, specialized protein networks that separate apical and basolateral membrane domains [6].Information regarding the composition of food flows from the apical to the basolateral doma
Marine Toxins That Target Voltage-gated Sodium Channels  [PDF]
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.
A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2  [PDF]
Stanislav Sokolov,Peter C. Ruben
Frontiers in Pharmacology , 2013, DOI: 10.3389/fphar.2013.00121
Abstract: Epilepsy is a disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels (NaVs). The C121W mutation of the β1 subunit, in particular, gives rise to the thermosensitive generalized epilepsy with febrile seizures plus (GEFS+) phenotype. Lacosamide is used to treat epileptic seizures and is distinct from other anti-seizure drugs by targeting NaV slow-inactivation. We studied the effects of a physiologically relevant concentration of lacosamide on the biophysical properties of NaV1.2 channels associated with either WT-β1 or the mutant C121W-β1 subunit. Biophysical parameters were measured at both normal (22°C) and elevated (34°C) temperatures to elicit the differential temperature-sensitivity of C121W. Lacosamide was more effective in NaV1.2 associated with the WT-β1 than with C121W-β1 at either temperature. There is also a more potent effect by lacosamide on slow inactivation at elevated temperatures. Our data suggest a modulatory role is imparted by the β1 subunit in the interaction between the drug and the channel.
The Structural Basis and Functional Consequences of Interactions Between Tetrodotoxin and Voltage-Gated Sodium Channels  [PDF]
Shana L. Geffeney,C. Ruben
Marine Drugs , 2006, DOI: 10.3390/md403143
Abstract: Tetrodotoxin (TTX) is a highly specific blocker of voltage-gated sodium channels. The dissociation constant of block varies with different channel isoforms. Until recently, channel resistance was thought to be primarily imparted by amino acid substitutions at a single position in domain I. Recent work reveals a novel site for tetrodotoxin resistance in the P-region of domain IV.
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