EMBO Molecular Medicine (Apr 2020)
A high‐affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain
- 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
Affiliations
- Nikolaj R Christensen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Marta De Luca
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Michael B Lever
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Mette Richner
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic‐EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University
- Astrid B Hansen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Gith Noes‐Holt
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Kathrine L Jensen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Mette Rathje
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Dennis Bo Jensen
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Simon Erlendsson
- Structural biology and NMR Laboratory, Department of Biology, University of Copenhagen
- Christian RO Bartling
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen
- Ina Ammendrup‐Johnsen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Sofie E Pedersen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Michèle Schönauer
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen
- Klaus B Nissen
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen
- Søren R Midtgaard
- Structural Biophysics, Niels Bohr Institute, University of Copenhagen
- Kaare Teilum
- Structural biology and NMR Laboratory, Department of Biology, University of Copenhagen
- Lise Arleth
- Structural Biophysics, Niels Bohr Institute, University of Copenhagen
- Andreas T Sørensen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Anders Bach
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen
- Kristian Strømgaard
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen
- Claire F Meehan
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Christian B Vægter
- Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic‐EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University
- Ulrik Gether
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- Kenneth L Madsen
- Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen
- DOI
- https://doi.org/10.15252/emmm.201911248
- Journal volume & issue
-
Vol. 12,
no. 6
pp. 1 – 25
Abstract
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.
Keywords
- biopharmaceuticals
- calcium permeable AMPARs
- maladaptive plasticity
- scaffold proteins
- synaptic plasticity
