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  1. Article ; Online: Molecular determinants of ASIC1 modulation by divalent cations.

    Liu, Yi / Ma, Jichun / DesJarlais, Renee L / Hagan, Rebecca / Rech, Jason / Liu, Changlu / Miller, Robyn / Schoellerman, Jeffrey / Luo, Jinquan / Letavic, Michael / Grasberger, Bruce / Maher, Michael P

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 2320

    Abstract: Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. ASIC gating is modulated by divalent cations as well as small molecules; however, the molecular determinants of gating modulation by divalent ... ...

    Abstract Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. ASIC gating is modulated by divalent cations as well as small molecules; however, the molecular determinants of gating modulation by divalent cations are not well understood. Previously, we identified two small molecules that bind to ASIC1a at a novel site in the acidic pocket and modulate ASIC1 gating in a manner broadly resembling divalent cations, raising the possibility that these small molecules may help to illuminate the molecular determinants of gating modulation by divalent cations. Here, we examined how these two groups of modulators might interact as well as mutational effects on ASIC1a gating and its modulation by divalent cations. Our results indicate that binding of divalent cations to an acidic pocket site plays a key role in gating modulation of the channel.
    MeSH term(s) Cations, Divalent/metabolism ; Acid Sensing Ion Channels/metabolism ; Protons ; Mutation
    Chemical Substances Cations, Divalent ; Acid Sensing Ion Channels ; Protons
    Language English
    Publishing date 2024-01-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-52845-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a).

    Liu, Yi / Hagan, Rebecca / Schoellerman, Jeffrey

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 7179

    Abstract: Acid-Sensing Ion Channels (ASICs) are gated by extracellular protons and play important roles in physiological and pathological states, such as pain and stroke. ASIC1a and ASIC2a, two of the most highly expressed subunits in the brain, form functional ... ...

    Abstract Acid-Sensing Ion Channels (ASICs) are gated by extracellular protons and play important roles in physiological and pathological states, such as pain and stroke. ASIC1a and ASIC2a, two of the most highly expressed subunits in the brain, form functional homo- and hetero-meric (ASIC1a/2a) channels. The function of ASIC1a has been widely studied using psalmotoxin (PcTx1), a venom-derived peptide, as an ASIC1a-selective antagonist. Here, using whole-cell patch clamp, we show that PcTx1 has dual actions at ASIC1a/2a. It can either inhibit or potentiate the heteromeric channel, depending on the conditioning and stimulating pHs. Potent inhibition occurs only at conditioning pHs that begin to desensitize the channel (IC
    MeSH term(s) Acid Sensing Ion Channels/chemistry ; Acid Sensing Ion Channels/drug effects ; Animals ; Brain/drug effects ; Brain/metabolism ; Brain/physiopathology ; CHO Cells ; Cricetulus ; Hydrogen-Ion Concentration ; Mice ; Neurons/drug effects ; Neurons/metabolism ; Patch-Clamp Techniques ; Peptides/chemistry ; Peptides/pharmacology ; Rats ; Spider Venoms/chemistry ; Spider Venoms/pharmacology
    Chemical Substances Accn1 protein, rat ; Acid Sensing Ion Channels ; Asic1 protein, rat ; PcTX1 protein, Psalmopoeus cambridgei ; Peptides ; Spider Venoms
    Language English
    Publishing date 2018-05-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-25386-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Discovery of a Series of Substituted 1

    Gelin, Christine F / Stenne, Brice / Coate, Heather / Hiscox, Afton / Soyode-Johnson, Akinola / Wall, Jessica L / Lord, Brian / Schoellerman, Jeffrey / Coe, Kevin J / Wang, Kai / Alcázar, Jesus / Chrovian, Christa C / Dvorak, Curt A / Carruthers, Nicholas I / Koudriakova, Tatiana / Balana, Bartosz / Letavic, Michael A

    Journal of medicinal chemistry

    2023  Volume 66, Issue 4, Page(s) 2877–2892

    Abstract: Herein, we describe a series of substituted ... ...

    Abstract Herein, we describe a series of substituted 1
    MeSH term(s) Animals ; Rats ; Brain/metabolism ; Pyrimidines ; Receptors, N-Methyl-D-Aspartate/metabolism ; Structure-Activity Relationship
    Chemical Substances NR2B NMDA receptor ; Pyrimidines ; Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2023-02-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.2c01916
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1.

    Liu, Yi / Ma, Jichun / DesJarlais, Renee L / Hagan, Rebecca / Rech, Jason / Lin, David / Liu, Changlu / Miller, Robyn / Schoellerman, Jeffrey / Luo, Jinquan / Letavic, Michael / Grasberger, Bruce / Maher, Michael

    Communications biology

    2021  Volume 4, Issue 1, Page(s) 174

    Abstract: Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key ... ...

    Abstract Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting.
    MeSH term(s) Acid Sensing Ion Channels/chemistry ; Acid Sensing Ion Channels/drug effects ; Acid Sensing Ion Channels/genetics ; Acid Sensing Ion Channels/metabolism ; Animals ; Binding Sites ; CHO Cells ; Cricetulus ; Ion Channel Gating/drug effects ; Kinetics ; Membrane Potentials ; Membrane Transport Modulators/chemistry ; Membrane Transport Modulators/pharmacology ; Mutation ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; Tachyphylaxis
    Chemical Substances Acid Sensing Ion Channels ; Asic1 protein, rat ; Membrane Transport Modulators
    Language English
    Publishing date 2021-02-09
    Publishing country England
    Document type Journal Article
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-021-01678-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Design, Synthesis, and Preclinical Evaluation of 3-Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5-

    Chrovian, Christa C / Soyode-Johnson, Akinola / Stenne, Brice / Pippel, Daniel J / Schoellerman, Jeffrey / Lord, Brian / Needham, Alexandra S / Xia, Chungfang / Coe, Kevin J / Sepassi, Kia / Schoetens, Freddy / Scott, Brian / Nguyen, Leslie / Jiang, Xiaohui / Koudriakova, Tatiana / Balana, Bartosz / Letavic, Michael A

    Journal of medicinal chemistry

    2020  Volume 63, Issue 17, Page(s) 9181–9196

    Abstract: Selective inhibitors of the GluN2B subunit ... ...

    Abstract Selective inhibitors of the GluN2B subunit of
    MeSH term(s) Allosteric Regulation ; Animals ; Antipsychotic Agents/chemical synthesis ; Antipsychotic Agents/pharmacokinetics ; Antipsychotic Agents/therapeutic use ; Brain/metabolism ; Dogs ; Drug Design ; Drug Evaluation, Preclinical ; Half-Life ; Humans ; Imidazoles/chemistry ; Imidazoles/pharmacokinetics ; Imidazoles/therapeutic use ; Male ; Mood Disorders/drug therapy ; Mood Disorders/pathology ; Nanostructures/chemistry ; Permeability/drug effects ; Pyridines/chemistry ; Pyridines/pharmacokinetics ; Pyridines/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/metabolism ; Solubility ; Structure-Activity Relationship
    Chemical Substances Antipsychotic Agents ; Imidazoles ; NR2B NMDA receptor ; Pyridines ; Receptors, N-Methyl-D-Aspartate ; imidazo(4,5-b)pyridine
    Language English
    Publishing date 2020-08-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.9b02113
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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  6. Article ; Online: Synchronous and asynchronous transmitter release at nicotinic synapses are differentially regulated by postsynaptic PSD-95 proteins.

    Neff, Robert A / Conroy, William G / Schoellerman, Jeffrey D / Berg, Darwin K

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2009  Volume 29, Issue 50, Page(s) 15770–15779

    Abstract: The rate and timing of information transfer at neuronal synapses are critical for determining synaptic efficacy and higher network function. Both synchronous and asynchronous neurotransmitter release shape the pattern of synaptic influences on a neuron. ... ...

    Abstract The rate and timing of information transfer at neuronal synapses are critical for determining synaptic efficacy and higher network function. Both synchronous and asynchronous neurotransmitter release shape the pattern of synaptic influences on a neuron. The PSD-95 family of postsynaptic scaffolding proteins, in addition to organizing postsynaptic components at glutamate synapses, acts transcellularly to regulate synchronous glutamate release. Here we show that PSD-95 family members at nicotinic synapses on chick ciliary ganglion neurons in culture execute multiple functions to enhance transmission. Together, endogenous PSD-95 and SAP102 in the postsynaptic cell appear to regulate transcellularly the synchronous release of transmitter from presynaptic terminals onto the neuron while stabilizing postsynaptic nicotinic receptor clusters under the release sites. Endogenous SAP97, in contrast, has no effect on receptor clusters but acts transcellularly from the postsynaptic cell through N-cadherin to enhance asynchronous release. These separate and parallel regulatory pathways allow postsynaptic scaffold proteins to dictate the pattern of cholinergic input a neuron receives; they also require balancing of PSD-95 protein levels to avoid disruptive competition that can occur through common binding domains.
    MeSH term(s) Animals ; Avian Proteins/antagonists & inhibitors ; Avian Proteins/genetics ; Avian Proteins/physiology ; Cell Line ; Cells, Cultured ; Chick Embryo ; Disks Large Homolog 4 Protein ; Excitatory Postsynaptic Potentials/physiology ; Ganglia, Parasympathetic/physiology ; Gene Knockdown Techniques ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/physiology ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/genetics ; Membrane Proteins/physiology ; Neurotransmitter Agents/genetics ; Neurotransmitter Agents/metabolism ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/genetics ; Nuclear Proteins/physiology ; RNA Interference ; Receptors, Nicotinic/genetics ; Receptors, Nicotinic/physiology ; Synapses/metabolism ; Synaptic Transmission/genetics ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics ; Transcription Factors/physiology
    Chemical Substances Avian Proteins ; DLG3 protein, human ; DLG4 protein, human ; Disks Large Homolog 4 Protein ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Neurotransmitter Agents ; Nuclear Proteins ; Receptors, Nicotinic ; Transcription Factors
    Language English
    Publishing date 2009-12-16
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.4951-09.2009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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