A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain

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DOI

  • Nikolaj R Christensen, University of Copenhagen
  • ,
  • Marta De Luca, University of Copenhagen
  • ,
  • Michael B Lever, University of Copenhagen
  • ,
  • Mette Richner
  • Astrid B Hansen, University of Copenhagen
  • ,
  • Gith Noes-Holt, University of Copenhagen
  • ,
  • Kathrine L Jensen, University of Copenhagen
  • ,
  • Mette Rathje, University of Copenhagen
  • ,
  • Dennis Bo Jensen, University of Copenhagen
  • ,
  • Simon Erlendsson, University of Copenhagen
  • ,
  • Christian Ro Bartling, University of Copenhagen
  • ,
  • Ina Ammendrup-Johnsen, University of Copenhagen
  • ,
  • Sofie E Pedersen, University of Copenhagen
  • ,
  • Michèle Schönauer, University of Copenhagen
  • ,
  • Klaus B Nissen, University of Copenhagen
  • ,
  • Søren R Midtgaard, University of Copenhagen
  • ,
  • Kaare Teilum, University of Copenhagen
  • ,
  • Lise Arleth, University of Copenhagen
  • ,
  • Andreas T Sørensen, University of Copenhagen
  • ,
  • Anders Bach, University of Copenhagen
  • ,
  • Kristian Strømgaard, University of Copenhagen
  • ,
  • Claire F Meehan, University of Copenhagen
  • ,
  • Christian B Vaegter
  • Ulrik Gether, University of Copenhagen
  • ,
  • Kenneth L Madsen, University of Copenhagen

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.

Original languageEnglish
Article number11248
JournalEMBO Molecular Medicine
Volume12
Number of pages25
ISSN1757-4676
DOIs
Publication statusPublished - Apr 2020

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