TY - JOUR
T1 - A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain
AU - Christensen, Nikolaj R.
AU - De Luca, Marta
AU - Lever, Michael B.
AU - Richner, Mette
AU - Hansen, Astrid B.
AU - Noes-Holt, Gith
AU - Jensen, Kathrine L.
AU - Rathje, Mette
AU - Jensen, Dennis Bo
AU - Erlendsson, Simon
AU - Bartling, Christian R.O.
AU - Ammendrup-Johnsen, Ina
AU - Pedersen, Sofie E.
AU - Schönauer, Michèle
AU - Nissen, Klaus B.
AU - Midtgaard, Søren R.
AU - Teilum, Kaare
AU - Arleth, Lise
AU - Sørensen, Andreas T.
AU - Bach, Anders
AU - Strømgaard, Kristian
AU - Meehan, Claire F.
AU - Vægter, Christian B.
AU - Gether, Ulrik
AU - Madsen, Kenneth L.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - biopharmaceuticals
KW - calcium permeable AMPARs
KW - maladaptive plasticity
KW - scaffold proteins
KW - synaptic plasticity
U2 - 10.15252/emmm.201911248
DO - 10.15252/emmm.201911248
M3 - Journal article
C2 - 32352640
AN - SCOPUS:85084202280
VL - 12
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 6
M1 - e11248
ER -