Defining the Kv2.1-syntaxin molecular interaction identifies a first-in-class small molecule neuroprotectant
The neuronal cell death-promoting loss of cytoplasmic K following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this int...
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| Vydané v: | Proceedings of the National Academy of Sciences - PNAS Ročník 116; číslo 31; s. 15696 |
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| Hlavní autori: | , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
30.07.2019
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| ISSN: | 1091-6490, 1091-6490 |
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| Abstract | The neuronal cell death-promoting loss of cytoplasmic K
following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection. |
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| AbstractList | The neuronal cell death-promoting loss of cytoplasmic K+ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection.The neuronal cell death-promoting loss of cytoplasmic K+ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection. The neuronal cell death-promoting loss of cytoplasmic K following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection. |
| Author | Yeh, Chung-Yang Moutal, Aubin Tzounopoulos, Thanos Camacho, Carlos J Khanna, Rajesh Ye, Zhaofeng Gaur, Shivani Henton, Amanda M Aizenman, Elias Saloman, Jami L Hartnett-Scott, Karen A Kouvaros, Stylianos |
| Author_xml | – sequence: 1 givenname: Chung-Yang orcidid: 0000-0002-0970-1300 surname: Yeh fullname: Yeh, Chung-Yang organization: Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 2 givenname: Zhaofeng surname: Ye fullname: Ye, Zhaofeng organization: School of Medicine, Tsinghua University, Beijing 100871, China – sequence: 3 givenname: Aubin orcidid: 0000-0003-4268-1206 surname: Moutal fullname: Moutal, Aubin organization: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724 – sequence: 4 givenname: Shivani surname: Gaur fullname: Gaur, Shivani organization: Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 5 givenname: Amanda M surname: Henton fullname: Henton, Amanda M organization: Pittsburgh Hearing Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 6 givenname: Stylianos surname: Kouvaros fullname: Kouvaros, Stylianos organization: Pittsburgh Hearing Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 7 givenname: Jami L orcidid: 0000-0001-6093-6511 surname: Saloman fullname: Saloman, Jami L organization: Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 8 givenname: Karen A surname: Hartnett-Scott fullname: Hartnett-Scott, Karen A organization: Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 9 givenname: Thanos surname: Tzounopoulos fullname: Tzounopoulos, Thanos organization: Pittsburgh Hearing Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 10 givenname: Rajesh orcidid: 0000-0002-9066-2969 surname: Khanna fullname: Khanna, Rajesh organization: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724 – sequence: 11 givenname: Elias surname: Aizenman fullname: Aizenman, Elias email: redox@pitt.edu, ccamacho@pitt.edu organization: Pittsburgh Hearing Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 – sequence: 12 givenname: Carlos J surname: Camacho fullname: Camacho, Carlos J email: redox@pitt.edu, ccamacho@pitt.edu organization: Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; redox@pitt.edu ccamacho@pitt.edu |
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following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This... The neuronal cell death-promoting loss of cytoplasmic K+ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This... |
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| SubjectTerms | Animals Brain - metabolism Munc18 Proteins - metabolism Neuroprotective Agents - chemistry Neuroprotective Agents - pharmacology Rats Shab Potassium Channels - metabolism SNARE Proteins - metabolism Syntaxin 1 - metabolism |
| Title | Defining the Kv2.1-syntaxin molecular interaction identifies a first-in-class small molecule neuroprotectant |
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