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Mouse taste cells with G protein-coupled taste receptors lack voltage-gated calcium channels and SNAP-25
Tod R Clapp, Kathryn F Medler, Sami Damak, Robert F Margolskee, Sue C Kinnamon
BMC Biology , 2006, DOI: 10.1186/1741-7007-4-7
Abstract: Depolarization with high K+ resulted in an increase in intracellular Ca2+ in a small subset of non-GFP labeled cells of both transgenic mouse lines. In contrast, no depolarization-evoked Ca2+ responses were observed in GFP-expressing taste cells of either genotype, but GFP-labeled cells responded to the PLC activator m-3M3FBS, suggesting that these cells were viable. Whole cell recording indicated that the GFP-labeled cells of both genotypes had small voltage-dependent Na+ and K+ currents, but no evidence of Ca2+ currents. A subset of non-GFP labeled taste cells exhibited large voltage-dependent Na+ and K+ currents and a high threshold voltage-gated Ca2+ current. Immunocytochemistry indicated that SNAP-25 was expressed in a separate population of taste cells from those expressing T1R3 or TRPM5. These data indicate that G protein-coupled taste receptors and conventional synaptic signaling mechanisms are expressed in separate populations of taste cells.The taste receptor cells responsible for the transduction of bitter, sweet, and umami stimuli are unlikely to communicate with nerve fibers by using conventional chemical synapses.Taste buds, the transducing elements of gustatory sensation, contain a heterogeneous population of 50 to 100 elongate taste receptor cells, which extend from the basal lamina to the surface of the epithelium. Taste stimuli interact with receptors on the apical membrane, while the basolateral membranes of some taste cells associate with gustatory nerve fibers to transmit taste information to the brain.Several types of taste cells have been identified morphologically. Type I cells, also known as "dark" cells, generally comprise about half of the taste bud. These cells are not believed to have a receptive function, but to play a more glial-like role in the taste bud [1,2]. About 35% of the cells are Type II cells, which are also known as "light" cells due to the electron lucent nature of their cytoplasm. Type II cells express T1R and T2R taste re
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.
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.
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.
Targeting voltage-gated sodium channels for treatment for chronic visceral pain  [cached]
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.
Amiloride-sensitive channels in type I fungiform taste cells in mouse
Aurelie Vandenbeuch, Tod R Clapp, Sue C Kinnamon
BMC Neuroscience , 2008, DOI: 10.1186/1471-2202-9-1
Abstract: Taste cell types were identified by their response to depolarizing voltage steps and their presence or absence of GFP fluorescence. TRPM5-GFP taste cells expressed large voltage-gated Na+ and K+ currents, but lacked voltage-gated Ca2+ currents, as expected from previous studies. Approximately half of the unlabeled cells had similar membrane properties, suggesting they comprise a separate population of Type II cells. The other half expressed voltage-gated outward currents only, typical of Type I cells. A single taste cell had voltage-gated Ca2+ current characteristic of Type III cells. Responses to amiloride occurred only in cells that lacked voltage-gated inward currents. Immunocytochemistry showed that fungiform taste buds have significantly fewer Type II cells expressing PLC signalling components, and significantly fewer Type III cells than circumvallate taste buds.The principal finding is that amiloride-sensitive Na+ channels appear to be expressed in cells that lack voltage-gated inward currents, likely the Type I taste cells. These cells were previously assumed to provide only a support function in the taste bud.At the peripheral taste system level, it is still unclear whether each taste quality is transduced by a separate population of taste cells, each connected to distinct nerve fibers (labelled-line model), or whether individual taste cells are sensitive to several taste modalities (across fiber pattern model). Currently, taste cells are categorized into three groups according to morphological, biochemical and physiological properties (for a review, see[1,2]). Type I cells make up about 50% of the total number of cells in a bud and are believed to have a support role, similar to glial cells in the nervous system. Type I cells wrap around other cells in the bud in a glial-like fashion [3]and express enzymes for inactivation and uptake of transmitters [4,5]. Notably, these cells have voltage-dependent outward currents, but they lack a voltage-gated inward cur
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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