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  1. Article ; Online: The Nicotinic Acetylcholine Receptor and its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level.

    Cecchini, Marco / Corringer, Pierre-Jean / Changeux, Jean-Pierre

    Annual review of biochemistry

    2024  

    Abstract: The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography ...

    Abstract The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo-electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system. Expected final online publication date for the
    Language English
    Publishing date 2024-02-12
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 207924-0
    ISSN 1545-4509 ; 0066-4154
    ISSN (online) 1545-4509
    ISSN 0066-4154
    DOI 10.1146/annurev-biochem-030122-033116
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  2. Article ; Online: Short-chain mono-carboxylates as negative modulators of allosteric transitions in Gloeobacter violaceus ligand-gated ion channel, and impact of a pre-β5 strand (Loop Ω) double mutation on crotonate, not butyrate effect.

    Van Renterghem, Catherine / Nemecz, Ákos / Medjebeur, Karima / Corringer, Pierre-Jean

    Physiological reports

    2024  Volume 12, Issue 3, Page(s) e15916

    Abstract: Using the bacterial proton-activated pentameric receptor-channel Gloeobacter violaceus ligand-gated ion channel (GLIC): (1) We characterize saturated, mono-carboxylates as negative modulators of GLIC (as previously shown for crotonate; Alqazzaz et al., ... ...

    Abstract Using the bacterial proton-activated pentameric receptor-channel Gloeobacter violaceus ligand-gated ion channel (GLIC): (1) We characterize saturated, mono-carboxylates as negative modulators of GLIC (as previously shown for crotonate; Alqazzaz et al., Biochemistry, 2016, 55, 5947). Butyrate and crotonate have indistinguishable properties regarding negative modulation of wt GLIC. (2) We identify a locus in the pre-β5 strand (Loop Ω) whose mutation inverses the effect of the mono-carboxylate crotonate from negative to positive modulation of the allosteric transitions, suggesting an involvement of the pre-β5 strand in coupling the extracellular orthotopic receptor to pore gating. (3) As an extension to the previously proposed "in series" mechanism, we suggest that a orthotopic/orthosteric site-vestibular site-Loop Ω-β5-β6 "sandwich"-Pro-Loop/Cys-Loop series may be an essential component of orthotopic/orthosteric compound-elicited gating control in this pentameric ligand-gated ion channel, on top of which compounds targeting the vestibular site may provide modulation.
    MeSH term(s) Crotonates ; Ligand-Gated Ion Channels/genetics ; Ligand-Gated Ion Channels/chemistry ; Butyrates ; Mutation ; Cyanobacteria
    Chemical Substances Crotonates ; Ligand-Gated Ion Channels ; Butyrates
    Language English
    Publishing date 2024-02-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2724325-4
    ISSN 2051-817X ; 2051-817X
    ISSN (online) 2051-817X
    ISSN 2051-817X
    DOI 10.14814/phy2.15916
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  3. Article ; Online: Fumarate as positive modulator of allosteric transitions in the pentameric ligand-gated ion channel GLIC: requirement of an intact vestibular pocket.

    Van Renterghem, Catherine / Nemecz, Ákos / Delarue-Cochin, Sandrine / Joseph, Delphine / Corringer, Pierre-Jean

    The Journal of physiology

    2023  Volume 601, Issue 12, Page(s) 2447–2472

    Abstract: Gloeobacter violaceus ligand-gated ion channel (GLIC) is a prokaryotic orthologue of brain pentameric neurotransmitter receptors. Using whole-cell patch-clamp electrophysiology in a host cell line, we show that short-chain dicarboxylate compounds are ... ...

    Abstract Gloeobacter violaceus ligand-gated ion channel (GLIC) is a prokaryotic orthologue of brain pentameric neurotransmitter receptors. Using whole-cell patch-clamp electrophysiology in a host cell line, we show that short-chain dicarboxylate compounds are positive modulators of pHo 5-evoked GLIC activity, with a rank order of action fumarate > succinate > malonate > glutarate. Potentiation by fumarate depends on intracellular pH, mainly as a result of a strong decrease of the pHo 5-evoked current when intracellular pH decreases. The modulating effect of fumarate also depends on extracellular pH, as fumarate is a weak inhibitor at pHo 6 and shows no agonist action at neutral pHo. A mutational analysis of residue dependency for succinate and fumarate effects, based on two carboxylate-binding pockets previously identified by crystallography (Fourati et al., 2020), shows that positive modulation involves both the inter-subunit pocket, homologous to the neurotransmitter-binding orthotopic site, and the intra-subunit (also called vestibular) pocket. An almost similar pattern of mutational impact is observed for the effect of caffeate, a known negative modulator. We propose, for both dicarboxylate compounds and caffeate, a model where the inter-subunit pocket is the actual binding site, and the region corresponding to the vestibular pocket is required either for inter-subunit binding itself, or for binding-to-gating coupling during the allosteric transitions involved in pore-gating modulation. KEY POINTS: Using a bacterial orthologue of brain pentameric neurotransmitter receptors, we show that the orthotopic/orthosteric agonist site and the adjacent vestibular region are functionally interdependent in mediating compound-elicited modulation. We propose that the two sites in the extracellular domain are involved 'in series', a mechanism which may have relevance for eukaryote receptors. We show that short-chain dicarboxylate compounds are positive modulators of the Gloeobacter violaceus ligand-gated ion channel (GLIC). The most potent compound identified is fumarate, known to occupy the orthotopic/orthosteric site in previously published crystal structures. We show that intracellular pH modulates GLIC allosteric transitions, as previously known for extracellular pH. We report a caesium to sodium permeability ratio (P
    MeSH term(s) Ligand-Gated Ion Channels/chemistry ; Cyanobacteria/metabolism ; Receptors, Neurotransmitter/metabolism ; Succinates/metabolism ; Bacterial Proteins/metabolism
    Chemical Substances Ligand-Gated Ion Channels ; Receptors, Neurotransmitter ; Succinates ; Bacterial Proteins
    Language English
    Publishing date 2023-04-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP283765
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  4. Article ; Online: Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway.

    Cerdan, Adrien H / Peverini, Laurie / Changeux, Jean-Pierre / Corringer, Pierre-Jean / Cecchini, Marco

    Science advances

    2022  Volume 8, Issue 41, Page(s) eadc9340

    Abstract: Glycine receptors (GlyRs) are ligand-gated ion channels mediating signal transduction at chemical synapses. Since the early patch-clamp electrophysiology studies, the details of the ion permeation mechanism have remained elusive. Here, we combine ... ...

    Abstract Glycine receptors (GlyRs) are ligand-gated ion channels mediating signal transduction at chemical synapses. Since the early patch-clamp electrophysiology studies, the details of the ion permeation mechanism have remained elusive. Here, we combine molecular dynamics simulations of a zebrafish GlyR-α1 model devoid of the intracellular domain with mutagenesis and single-channel electrophysiology of the full-length human GlyR-α1. We show that lateral fenestrations between subunits in the extracellular domain provide the main translocation pathway for chloride ions to enter/exit a central water-filled vestibule at the entrance of the transmembrane channel. In addition, we provide evidence that these fenestrations are at the origin of current rectification in known anomalous mutants and design de novo two inward-rectifying channels by introducing mutations within them. These results demonstrate the central role of lateral fenestrations on synaptic neurotransmission.
    Language English
    Publishing date 2022-10-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adc9340
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  5. Article ; Online: The desensitization pathway of GABA

    Gielen, Marc / Barilone, Nathalie / Corringer, Pierre-Jean

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 5369

    Abstract: ... ...

    Abstract GABA
    MeSH term(s) Animals ; Computer Simulation ; Ion Channels ; Ion Transport ; Kinetics ; Models, Molecular ; Molecular Conformation ; Mutation ; Nervous System/metabolism ; Oocytes ; Protein Conformation ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Receptors, GABA-A/chemistry ; Receptors, GABA-A/genetics ; Receptors, GABA-A/metabolism ; Synaptic Transmission/physiology ; Xenopus laevis/metabolism
    Chemical Substances Ion Channels ; Protein Subunits ; Receptors, GABA-A
    Language English
    Publishing date 2020-10-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-19218-6
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  6. Article ; Online: The dual-gate model for pentameric ligand-gated ion channels activation and desensitization.

    Gielen, Marc / Corringer, Pierre-Jean

    The Journal of physiology

    2018  Volume 596, Issue 10, Page(s) 1873–1902

    Abstract: Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. ... ...

    Abstract Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. Understanding their biophysical and pharmacological properties, at both the functional and the structural level, thus holds many therapeutic promises. In addition to their agonist-elicited activation, most pLGICs display another key allosteric property, namely desensitization, in which they enter a shut state refractory to activation upon sustained agonist binding. While the activation mechanisms of several pLGICs have been revealed at near-atomic resolution, the structural foundation of desensitization has long remained elusive. Recent structural and functional data now suggest that the activation and desensitization gates are distinct, and are located at both sides of the ion channel. Such a 'dual gate mechanism' accounts for the marked allosteric effects of channel blockers, a feature illustrated herein by theoretical kinetics simulations. Comparison with other classes of ligand- and voltage-gated ion channels shows that this dual gate mechanism emerges as a common theme for the desensitization and inactivation properties of structurally unrelated ion channels.
    MeSH term(s) Animals ; Humans ; Ion Channel Gating ; Ligand-Gated Ion Channels/chemistry ; Ligand-Gated Ion Channels/drug effects ; Ligand-Gated Ion Channels/physiology ; Ligands ; Models, Molecular ; Neurotransmitter Agents/pharmacology ; Protein Conformation
    Chemical Substances Ligand-Gated Ion Channels ; Ligands ; Neurotransmitter Agents
    Language English
    Publishing date 2018-04-17
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP275100
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  7. Article ; Online: The desensitization pathway of GABAA receptors, one subunit at a time

    Marc Gielen / Nathalie Barilone / Pierre-Jean Corringer

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: GABAA receptors mediate most inhibitory synaptic transmission in the brain. Here authors used concatemeric α1β2γ2 GABAA receptors to introduce gain-of-desensitization mutations one subunit at a time, revealing non-concerted rearrangements with a key ... ...

    Abstract GABAA receptors mediate most inhibitory synaptic transmission in the brain. Here authors used concatemeric α1β2γ2 GABAA receptors to introduce gain-of-desensitization mutations one subunit at a time, revealing non-concerted rearrangements with a key contribution of the γ2 subunit during desensitization.
    Keywords Science ; Q
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: The desensitization pathway of GABAA receptors, one subunit at a time

    Marc Gielen / Nathalie Barilone / Pierre-Jean Corringer

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: GABAA receptors mediate most inhibitory synaptic transmission in the brain. Here authors used concatemeric α1β2γ2 GABAA receptors to introduce gain-of-desensitization mutations one subunit at a time, revealing non-concerted rearrangements with a key ... ...

    Abstract GABAA receptors mediate most inhibitory synaptic transmission in the brain. Here authors used concatemeric α1β2γ2 GABAA receptors to introduce gain-of-desensitization mutations one subunit at a time, revealing non-concerted rearrangements with a key contribution of the γ2 subunit during desensitization.
    Keywords Science ; Q
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
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  9. Article ; Online: Conformational state-dependent regulation of GABA

    Merlaud, Zaha / Marques, Xavier / Russeau, Marion / Saade, Ursula / Tostain, Maelys / Moutkine, Imane / Gielen, Marc / Corringer, Pierre-Jean / Lévi, Sabine

    iScience

    2022  Volume 25, Issue 11, Page(s) 105467

    Abstract: The efficacy of GABAergic synapses relies on the number of postsynaptic ... ...

    Abstract The efficacy of GABAergic synapses relies on the number of postsynaptic GABA
    Language English
    Publishing date 2022-10-29
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2022.105467
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  10. Article ; Online: Illumination of a progressive allosteric mechanism mediating the glycine receptor activation.

    Shi, Sophie / Lefebvre, Solène N / Peverini, Laurie / Cerdan, Adrien H / Milán Rodríguez, Paula / Gielen, Marc / Changeux, Jean-Pierre / Cecchini, Marco / Corringer, Pierre-Jean

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 795

    Abstract: Pentameric ligand-gated ion channel mediate signal transduction at chemical synapses by transiting between resting and open states upon neurotransmitter binding. Here, we investigate the gating mechanism of the glycine receptor fluorescently labeled at ... ...

    Abstract Pentameric ligand-gated ion channel mediate signal transduction at chemical synapses by transiting between resting and open states upon neurotransmitter binding. Here, we investigate the gating mechanism of the glycine receptor fluorescently labeled at the extracellular-transmembrane interface by voltage-clamp fluorometry (VCF). Fluorescence reports a glycine-elicited conformational change that precedes pore opening. Low concentrations of glycine, partial agonists or specific mixtures of glycine and strychnine trigger the full fluorescence signal while weakly activating the channel. Molecular dynamic simulations of a partial agonist bound-closed Cryo-EM structure show a highly dynamic nature: a marked structural flexibility at both the extracellular-transmembrane interface and the orthosteric site, generating docking properties that recapitulate VCF data. This work illuminates a progressive propagating transition towards channel opening, highlighting structural plasticity within the mechanism of action of allosteric effectors.
    MeSH term(s) Receptors, Glycine/metabolism ; Glycine/pharmacology ; Lighting ; Molecular Dynamics Simulation ; Signal Transduction
    Chemical Substances Receptors, Glycine ; Glycine (TE7660XO1C)
    Language English
    Publishing date 2023-02-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-36471-7
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