A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain
Abstract Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) pep...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-04-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201911248 |
| _version_ | 1827015218168856576 |
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| author | Nikolaj R Christensen Marta De Luca Michael B Lever Mette Richner Astrid B Hansen Gith Noes‐Holt Kathrine L Jensen Mette Rathje Dennis Bo Jensen Simon Erlendsson Christian RO Bartling Ina Ammendrup‐Johnsen Sofie E Pedersen Michèle Schönauer Klaus B Nissen Søren R Midtgaard Kaare Teilum Lise Arleth Andreas T Sørensen Anders Bach Kristian Strømgaard Claire F Meehan Christian B Vægter Ulrik Gether Kenneth L Madsen |
| author_facet | Nikolaj R Christensen Marta De Luca Michael B Lever Mette Richner Astrid B Hansen Gith Noes‐Holt Kathrine L Jensen Mette Rathje Dennis Bo Jensen Simon Erlendsson Christian RO Bartling Ina Ammendrup‐Johnsen Sofie E Pedersen Michèle Schönauer Klaus B Nissen Søren R Midtgaard Kaare Teilum Lise Arleth Andreas T Sørensen Anders Bach Kristian Strømgaard Claire F Meehan Christian B Vægter Ulrik Gether Kenneth L Madsen |
| author_sort | Nikolaj R Christensen |
| collection | DOAJ |
| description | Abstract Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P4‐(C5)2, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat‐P4‐(C5)2 disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA‐receptor surface expression in vivo. Moreover, Tat‐P4‐(C5)2 administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat‐P4‐(C5)2 as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non‐tandem protein–protein interaction domains. |
| first_indexed | 2024-03-07T17:53:54Z |
| format | Article |
| id | doaj.art-8a1820f6df8d4578a98d525b18b57606 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:59Z |
| publishDate | 2020-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-8a1820f6df8d4578a98d525b18b576062024-10-28T08:54:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-04-0112612510.15252/emmm.201911248A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic painNikolaj R Christensen0Marta De Luca1Michael B Lever2Mette Richner3Astrid B Hansen4Gith Noes‐Holt5Kathrine L Jensen6Mette Rathje7Dennis Bo Jensen8Simon Erlendsson9Christian RO Bartling10Ina Ammendrup‐Johnsen11Sofie E Pedersen12Michèle Schönauer13Klaus B Nissen14Søren R Midtgaard15Kaare Teilum16Lise Arleth17Andreas T Sørensen18Anders Bach19Kristian Strømgaard20Claire F Meehan21Christian B Vægter22Ulrik Gether23Kenneth L Madsen24Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDanish Research Institute of Translational Neuroscience (DANDRITE), Nordic‐EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus UniversityMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenStructural biology and NMR Laboratory, Department of Biology, University of CopenhagenCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of CopenhagenCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of CopenhagenStructural Biophysics, Niels Bohr Institute, University of CopenhagenStructural biology and NMR Laboratory, Department of Biology, University of CopenhagenStructural Biophysics, Niels Bohr Institute, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of CopenhagenCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDanish Research Institute of Translational Neuroscience (DANDRITE), Nordic‐EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus UniversityMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenMolecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenAbstract Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P4‐(C5)2, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat‐P4‐(C5)2 disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA‐receptor surface expression in vivo. Moreover, Tat‐P4‐(C5)2 administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat‐P4‐(C5)2 as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non‐tandem protein–protein interaction domains.https://doi.org/10.15252/emmm.201911248biopharmaceuticalscalcium permeable AMPARsmaladaptive plasticityscaffold proteinssynaptic plasticity |
| spellingShingle | Nikolaj R Christensen Marta De Luca Michael B Lever Mette Richner Astrid B Hansen Gith Noes‐Holt Kathrine L Jensen Mette Rathje Dennis Bo Jensen Simon Erlendsson Christian RO Bartling Ina Ammendrup‐Johnsen Sofie E Pedersen Michèle Schönauer Klaus B Nissen Søren R Midtgaard Kaare Teilum Lise Arleth Andreas T Sørensen Anders Bach Kristian Strømgaard Claire F Meehan Christian B Vægter Ulrik Gether Kenneth L Madsen A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain EMBO Molecular Medicine biopharmaceuticals calcium permeable AMPARs maladaptive plasticity scaffold proteins synaptic plasticity |
| title | A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain |
| title_full | A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain |
| title_fullStr | A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain |
| title_full_unstemmed | A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain |
| title_short | A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain |
| title_sort | high affinity bivalent pdz domain inhibitor complexes pick1 to alleviate neuropathic pain |
| topic | biopharmaceuticals calcium permeable AMPARs maladaptive plasticity scaffold proteins synaptic plasticity |
| url | https://doi.org/10.15252/emmm.201911248 |
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