Tarantula Toxins Use Common Surfaces for Interacting with Kv and ASIC
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UC Davis UC Davis Previously Published Works
UC Davis UC Davis Previously Published Works Title Heterogeneity in Kv2 Channel Expression Shapes Action Potential Characteristics and Firing Patterns in CA1 versus CA2 Hippocampal Pyramidal Neurons. Permalink https://escholarship.org/uc/item/2m94393j Journal eNeuro, 4(4) ISSN 2373-2822 Authors Palacio, Stephanie Chevaleyre, Vivien Brann, David H et al. Publication Date 2017-07-01 DOI 10.1523/ENEURO.0267-17.2017 Peer reviewed eScholarship.org Powered by the California Digital Library University of California New Research Neuronal Excitability Heterogeneity in Kv2 Channel Expression Shapes Action Potential Characteristics and Firing Patterns in CA1 versus CA2 Hippocampal Pyramidal Neurons Stephanie Palacio,1 Vivien Chevaleyre,2 David H. Brann,3 Karl D. Murray,4 Rebecca A. Piskorowski,2 and James S. Trimmer1,5 DOI:http://dx.doi.org/10.1523/ENEURO.0267-17.2017 1Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, 2INSERM U894, Team Synaptic Plasticity and Neural Networks, Université Paris Descartes, Paris 75014, France, 3Department of Neuroscience, Columbia University, New York, NY 10032, 4Center for Neuroscience, University of California, Davis, CA 95616, and 5Department of Physiology and Membrane Biology, University of California Davis School of Medicine, Davis, CA 95616 Abstract The CA1 region of the hippocampus plays a critical role in spatial and contextual memory, and has well- established circuitry, function and plasticity. In contrast, the properties of the flanking CA2 pyramidal neurons (PNs), important for social memory, and lacking CA1-like plasticity, remain relatively understudied. In particular, little is known regarding the expression of voltage-gated Kϩ (Kv) channels and the contribution of these channels to the distinct properties of intrinsic excitability, action potential (AP) waveform, firing patterns and neurotrans- mission between CA1 and CA2 PNs. -
Opening the Shaker K+ Channel with Hanatoxin
A r t i c l e Opening the Shaker K+ channel with hanatoxin Mirela Milescu,1 Hwa C. Lee,1 Chan Hyung Bae,2 Jae Il Kim,2 and Kenton J. Swartz1 1Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 2Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea Voltage-activated ion channels open and close in response to changes in membrane voltage, a property that is fundamental to the roles of these channels in electrical signaling. Protein toxins from venomous organisms com- monly target the S1–S4 voltage-sensing domains in these channels and modify their gating properties. Studies on the interaction of hanatoxin with the Kv2.1 channel show that this tarantula toxin interacts with the S1–S4 domain and inhibits opening by stabilizing a closed state. Here we investigated the interaction of hanatoxin with the Shaker Kv channel, a voltage-activated channel that has been extensively studied with biophysical approaches. In contrast to what is observed in the Kv2.1 channel, we find that hanatoxin shifts the conductance–voltage relation to negative voltages, making it easier to open the channel with membrane depolarization. Although these actions of the toxin are subtle in the wild-type channel, strengthening the toxin–channel interaction with mutations in the S3b helix of the S1-S4 domain enhances toxin affinity and causes large shifts in the conductance–voltage relation- ship. Using a range of previously characterized mutants of the Shaker Kv channel, we find that hanatoxin stabilizes an activated conformation of the voltage sensors, in addition to promoting opening through an effect on the final opening transition. -
Life-Style Related Disease Antibodies Kits Diabetes & Obesities
BIO-No.2 Wako Product Update Bio-No.2 Life-style related Disease Kits Antibodies Diabetes & Obesities INDEX 1. Kits 3. Reagents for Diabetes Research 1Kit Index ............................................................ 3 3-a Kv2.1/Kv2.2 Channel Blocker / Enhancer of 1-a Adiponectin ...................................................... 4 Glucose-Dependent Insulin Secretion ......... 18 1-b A/G ratio............................................................ 4 3-b Sulfonylurea (SU) Antidiabetic Agents ......... 18 1-c Albumin ............................................................. 5 3-c Biguanide Antidiabetic Agents ...................... 18 1-d Alkaline Phosphatase ..................................... 6 3-d Diabetes Complication ................................... 19 1-e Apo B-48 ........................................................... 6 3-e Glucagon Like Peptides .................................. 19 1-f CETP .................................................................. 7 3-f Resistance to Insulin ....................................... 19 Research Diabetes Reagents for Reagents 1-g C-Peptide .......................................................... 8 3-g Others ............................................................... 20 C-Peptide 8 4. Reagents for Hyperlipidemia Research C-Peptide High Sensitive 8 4-a Reagents for Hyperlipidemia Research........ 21 1-h Creatinine ......................................................... 9 HMG-CoA Reductase Inhibitors 21 1-i Glucagon .......................................................... -
Optical Measurement of Endogenous Ion Channel Voltage Sensor Activation in Tissue
bioRxiv preprint doi: https://doi.org/10.1101/541805; this version posted September 5, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Optical measurement of endogenous ion channel voltage sensor activation in tissue Authors Parashar Thapa1‡, Robert Stewart1‡, Rebecka J. Sepela1, Oscar Vivas2, Laxmi K. Parajuli2, Mark Lillya1, Sebastian Fletcher-Taylor1, Bruce E. Cohen3, Karen Zito2, Jon T. Sack1* 1Department of Physiology and Membrane Biology, University of California, Davis, CA 95616 2Center for Neuroscience, University of California, Davis, CA 95616 3Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 ‡Authors contributed equally to this work *Correspondence to [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/541805; this version posted September 5, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Abstract 2 A primary goal of molecular physiology is to understand how conformational changes of 3 proteins affect the function of cells, tissues, and organisms. Here, we describe an imaging 4 method for measuring the conformational changes of a voltage-sensing protein within tissue. We 5 synthesized a fluorescent molecular probe, compatible with two-photon microscopy, that targets 6 a resting conformation of Kv2-type voltage gated K+ channel proteins. Voltage-response 7 characteristics were used to calibrate a statistical thermodynamic model relating probe labeling 8 intensity to the conformations adopted by unlabeled Kv2 proteins. Two-photon imaging of rat 9 brain slices labeled with the probe revealed fluorescence consistent with conformation-selective 10 labeling of endogenous neuronal Kv2 proteins. -
Functional Roles of Kv1-Mediated Currents in Genetically Identified
J Neurophysiol 120: 394–408, 2018. First published April 11, 2018; doi:10.1152/jn.00691.2017. RESEARCH ARTICLE Cellular and Molecular Properties of Neurons Functional roles of Kv1-mediated currents in genetically identified subtypes of pyramidal neurons in layer 5 of mouse somatosensory cortex Dongxu Guan, Dhruba Pathak, and Robert C. Foehring Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee Submitted 20 September 2017; accepted in final form 3 April 2018 Guan D, Pathak D, Foehring RC. Functional roles of Kv1- that PN properties vary with cortical layer and synaptic targets. mediated currents in genetically identified subtypes of pyramidal PNs in layer 5 have been classified on the basis of morphology neurons in layer 5 of mouse somatosensory cortex. J Neurophysiol and laminar position, projection patterns, and firing patterns 120: 394–408, 2018. First published April 11, 2018; doi:10.1152/ jn.00691.2017.—We used voltage-clamp recordings from somatic (Chagnac-Amitai et al. 1990; Christophe et al. 2005; Dembrow outside-out macropatches to determine the amplitude and biophysical et al. 2010; Hattox and Nelson 2007; Ivy and Killackey 1982; properties of putative Kv1-mediated currents in layer 5 pyramidal Kasper et al. 1994; Larkman and Mason 1990; Le Bé et al. neurons (PNs) from mice expressing EGFP under the control of 2007; Mason and Larkman 1990; Tseng and Prince 1993; Wise promoters for etv1 or glt. We then used whole cell current-clamp and Jones 1977). In somatosensory cortex, there is high con- recordings and Kv1-specific peptide blockers to test the hypothesis cordance of these different schemes: large, thick-tufted PNs in that Kv1 channels differentially regulate action potential (AP) voltage deep layer 5 project beyond the telencephalon (pyramidal tract threshold, repolarization rate, and width as well as rheobase and repetitive firing in these two PN types. -
Targeting Voltage Sensors in Sodium Channels with Spider Toxins
Review Targeting voltage sensors in sodium channels with spider toxins Frank Bosmans1,2 and Kenton J. Swartz1 1 Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA 2 Laboratory of Toxicology, University of Leuven, 3000 Leuven, Belgium Voltage-activated sodium (Nav) channels are essential more distantly related Nav channels (e.g. Nav1.8 and in generating and propagating nerve impulses, placing Nav1.9) have distinct operational mechanisms. them amongst the most widely targeted ion channels Nav channels are one of the foremost targets of mol- by toxins from venomous organisms. An increasing ecules present in animal venoms [13] . Toxins from scor- number of spider toxins have been shown to interfere pions and sea anemones, as well as venoms from cone with the voltage-driven activation process of mamma- snails, have been used to describe various receptor sites lian Nav channels, possibly by interacting with one or in different regions of the channel [14–17]. However, the more of their voltage sensors. This review focuses on exploration of the mechanism through which spider toxins our existing knowledge of the mechanism by which interact with mammalian Nav channels has only recently spider toxins affect Nav channel gating and the begun. This is in contrast to voltage-activated potassium possible applications of these toxins in the drug (Kv) channels, where tarantula toxins such as hanatoxin discovery process. from Grammostola spatulata have been used extensively to study the functional properties of these channels [18–21]. Introduction Evidence demonstrating that tarantula toxins modify the + Voltage-activated sodium (Nav) channels are Na -per- opening and closing (‘gating’) of Kv channels by influencing meable ion channels that open and close in response to their voltage sensors comes from three observations. -
Structure of the Acid-Sensing Ion Channel 1 in Complex with the Gating Modifi Er Psalmotoxin 1
ARTICLE Received 17 Jan 2012 | Accepted 18 May 2012 | Published 3 Jul 2012 DOI: 10.1038/ncomms1917 Structure of the Acid-sensing ion channel 1 in complex with the gating modifi er Psalmotoxin 1 Roger J.P. Dawson1 , J ö r g B e n z1 , Peter Stohler1 , Tim Tetaz 1 , Catherine Joseph1 , Sylwia Huber 1 , Georg Schmid 1 , Daniela H ü gin 1 , Pascal Pfl imlin 2 , Gerd Trube 2 , Markus G. Rudolph1 , Michael Hennig 1 & A r m i n R u f 1 Venom-derived peptide toxins can modify the gating characteristics of excitatory channels in neurons. How they bind and interfere with the fl ow of ions without directly blocking the ion permeation pathway remains elusive. Here we report the crystal structure of the trimeric chicken Acid-sensing ion channel 1 in complex with the highly selective gating modifi er Psalmotoxin 1 at 3.0 Å resolution. The structure reveals the molecular interactions of three toxin molecules binding at the proton-sensitive acidic pockets of Acid-sensing ion channel 1 and electron density consistent with a cation trapped in the central vestibule above the ion pathway. A hydrophobic patch and a basic cluster are the key structural elements of Psalmotoxin 1 binding, locking two separate regulatory regions in their relative, desensitized-like arrangement. Our results provide a general concept for gating modifi er toxin binding suggesting that both surface motifs are required to modify the gating characteristics of an ion channel. 1 F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Discovery Technologies , Grenzacherstrasse 124, Basel CH4070 , Switzerland . -
Hanatoxin Modifies the Gating of a Voltage-Dependent K Channel Through Multiple Binding Sites
Neuron, Vol. 18, 665±673, April, 1997, Copyright 1997 by Cell Press Hanatoxin Modifies the Gating of a Voltage-Dependent K1 Channel through Multiple Binding Sites Kenton J. Swartz*² and Roderick MacKinnon*³§ acid sequence, HaTx seems to have little in common *Department of Neurobiology with the previously described pore-blocking K1 channel Harvard Medical School inhibitors (Swartz and MacKinnon, 1995). By what mech- Boston, Massachusetts 02115 anism does HaTx inhibit voltage-gated K1 channels? §Laboratory of Molecular Neurobiology Voltage-gated K1 channels contain a K1 selective pore and Biophysics that opens and closes in response to changes in mem- The Rockefeller University brane voltage. So HaTx might inhibit the channel either New York, New York 10021 by physically plugging the pore or by interfering with the way that changes in membrane voltage control opening and closing of the pore. In the present paper, we de- Summary scribe experiments that address the mechanism of inhi- bition and the stoichiometry of the interaction between We studied the mechanism by which Hanatoxin (HaTx) HaTx and the drk1 K1 channel. Using a tail current proto- inhibits the drk1 voltage-gated K1 channel. HaTx inhib- col, we discovered that the drk1 K1 channel can open its the K1 channel by shifting channel opening to more with HaTx bound to it. Toxin bound channels require depolarized voltages. Channels opened by strong de- strong depolarization to open and deactivate much polarization in the presence of HaTx deactivate much faster upon repolarization, suggesting that HaTx inhibits faster upon repolarization, indicating that toxin bound by modifying the gating of the drk1 voltage-gated K1 channels can open. -
Versatile Spider Venom Peptides and Their Medical and Agricultural Applications
Accepted Manuscript Versatile spider venom peptides and their medical and agricultural applications Natalie J. Saez, Volker Herzig PII: S0041-0101(18)31019-5 DOI: https://doi.org/10.1016/j.toxicon.2018.11.298 Reference: TOXCON 6024 To appear in: Toxicon Received Date: 2 May 2018 Revised Date: 12 November 2018 Accepted Date: 14 November 2018 Please cite this article as: Saez, N.J., Herzig, V., Versatile spider venom peptides and their medical and agricultural applications, Toxicon (2019), doi: https://doi.org/10.1016/j.toxicon.2018.11.298. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT MANUSCRIPT ACCEPTED ACCEPTED MANUSCRIPT 1 Versatile spider venom peptides and their medical and agricultural applications 2 3 Natalie J. Saez 1, #, *, Volker Herzig 1, #, * 4 5 1 Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 4072, Australia 6 7 # joint first author 8 9 *Address correspondence to: 10 Dr Natalie Saez, Institute for Molecular Bioscience, The University of Queensland, St. Lucia QLD 11 4072, Australia; Phone: +61 7 3346 2011, Fax: +61 7 3346 2101, Email: [email protected] 12 Dr Volker Herzig, Institute for Molecular Bioscience, The University of Queensland, St. -
Product Datasheet Guangxitoxin 1E
Product Datasheet Guangxitoxin 1E Product name: Guangxitoxin 1E Synonyms : GxTx1E Catalog # : 11GUA002 Product description Guangxitoxin-1E (GxTx-1E) was isolated from the venom of Chilobrachys jingzhao (Chinese earth tiger tarantula). Guangxitoxin-1E was shown to block Kv2.1/KCNB1, Kv2.2/KCNB2 and Kv4.3/KCND3 channels without significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, Kv3.2/KCNC2, Cav1.2/CACNA1C, Cav2.2/CACNA1B, Nav1.5/SCN5A, Nav1.7/SCN9A or Nav1.8/SCN10A channels. Guangxitoxin-1E inhibits Kv2.1 with an IC50 value of 1 nM and Kv2.2 with an IC50 value of 3 nM. Block of Kv4.3 occurs at 10-20 fold higher concentrations. Guangxitoxin-1E acts as a gating modifier + since it shifts the voltage-dependence of Kv2.1 K currents towards depolarized potentials. In pancreatic beta-cells, Guangxitoxin-1E enhances glucose-stimulated insulin secretion by broadening the cell action potential and enhancing calcium oscillations. Product specifications AA sequence: Glu-Gly-Glu-Cys4-Gly-Gly-Phe-Trp-Trp-Lys-Cys11-Gly-Ser-Gly-Lys-Pro-Ala-Cys18-Cys19-Pro-Lys-Tyr-Val-Cys24- Ser-Pro-Lys-Trp-Gly-Leu-Cys31-Asn-Phe-Pro-Met-Pro-OH Disulfide bonds: Cys4-Cys19, Cys11-Cys24 and Cys18-Cys31 Length (aa): 36 Formula: C178H248N44O45S7 Appearance: White lyophilized solid Molecular Weight: 3948.72 Da CAS number: Source: Synthetic Counterion: TFA salts Solubility: Water or saline buffer, 5 mg/mL maximum (recommendation) Formulation Storage/Stability: Shipped at ambient temperature under lyophilized powder. Store at -20°C (-4°F). Do not freeze-thaw. Aliquot sample if required and store at -80°C (-112°F). -
An Imaging Method to Measure Conformational Changes of Voltage Sensors of Endogenous Ion Channels in Tissue
bioRxiv preprint doi: https://doi.org/10.1101/541805; this version posted February 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. An imaging method to measure conformational changes of voltage sensors of endogenous ion channels in tissue Authors Parashar Thapa1‡, Robert Stewart1‡, Rebecka J. Sepela1, Oscar Vivas2, Laxmi K. Parajuli2, Mark Lillya1, Sebastian Fletcher-Taylor1, Bruce E. Cohen3, Karen Zito2, Jon T. Sack1* 1Department of Physiology and Membrane Biology, University of California, Davis, CA 95616 2Center for Neuroscience, University of California, Davis, CA 95616 3Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 ‡Authors contributed equally to this work *Correspondence to [email protected] bioRxiv preprint doi: https://doi.org/10.1101/541805; this version posted February 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract A primary goal of molecular physiology is to understand the coupling between protein conformational change and systemic function. To see the conformational changes of a voltage- sensing protein within tissue, we synthesized a fluorescent molecular probe compatible with two-photon microscopy and developed a method to deconvolve conformational changes from fluorescence images. The probe was a fluorescently-tagged variant of a tarantula venom peptide that binds Kv2-type voltage gated K+ channel proteins when their voltage-sensing domains are in a resting conformation. Kv2 proteins in cell membranes were labeled by the probe, and the intensity of labeling responded to voltage changes. -
Inhibition of A-Type Potassium Current by the Peptide Toxin SNX-482
9182 • The Journal of Neuroscience, July 9, 2014 • 34(28):9182–9189 Cellular/Molecular Inhibition of A-Type Potassium Current by the Peptide Toxin SNX-482 Tilia Kimm and Bruce P. Bean Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 SNX-482, a peptide toxin isolated from tarantula venom, has become widely used as an inhibitor of Cav2.3 voltage-gated calcium channels. Unexpectedly, we found that SNX-482 dramatically reduced the A-type potassium current in acutely dissociated dopamine neurons from mouse substantia nigra pars compacta. The inhibition persisted when calcium was replaced by cobalt, showing that it was not secondary to a reduction of calcium influx. Currents from cloned Kv4.3 channels expressed in HEK-293 cells were inhibited by Ͻ SNX-482 with an IC50 of 3nM, revealing substantially greater potency than for SNX-482 inhibition of Cav2.3 channels (IC50 20–60nM). At sub-saturating concentrations, SNX-482 produced a depolarizing shift in the voltage dependence of activation of Kv4.3 channels and slowed activation kinetics. Similar effects were seen on gating of cloned Kv4.2 channels, but the inhibition was less pronounced and required higher toxin concentrations. These results reveal SNX-482 as the most potent inhibitor of Kv4.3 channels yet identified. Because of the effects on both Kv4.3 and Kv4.2 channels, caution is needed when interpreting the effects of SNX-482 on cells and circuits where these channels are present. Key words: Cav2.3; IA ; ICK toxin; Kv4.2; Kv4.3; tarantula toxin Introduction used to identify currents from Cav2.3 channels and to investigate Mammalian neurons express many different types of voltage- their functions in cells and circuits (Pringos et al., 2011).