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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

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

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.

OriginalsprogEngelsk
Artikelnummer11248
TidsskriftEMBO Molecular Medicine
Vol/bind12
Antal sider25
ISSN1757-4676
DOI
StatusUdgivet - apr. 2020

Bibliografisk note

© 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Se relationer på Aarhus Universitet Citationsformater

ID: 186044390