A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain
© 2020 The Authors. Published under the terms of the CC BY 4.0 license..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
EMBO molecular medicine - 12(2020), 6 vom: 08. Juni, Seite e11248 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Christensen, Nikolaj R [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 18.08.2021 Date Revised 31.05.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.15252/emmm.201911248 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM309363926 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM309363926 | ||
| 003 | DE-627 | ||
| 005 | 20231225133740.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.15252/emmm.201911248 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1031.xml |
| 035 | |a (DE-627)NLM309363926 | ||
| 035 | |a (NLM)32352640 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Christensen, Nikolaj R |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.08.2021 | ||
| 500 | |a Date Revised 31.05.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 The Authors. Published under the terms of the CC BY 4.0 license. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a biopharmaceuticals | |
| 650 | 4 | |a calcium permeable AMPARs | |
| 650 | 4 | |a maladaptive plasticity | |
| 650 | 4 | |a scaffold proteins | |
| 650 | 4 | |a synaptic plasticity | |
| 650 | 7 | |a Carrier Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a PICk1 protein, human |2 NLM | |
| 650 | 7 | |a Receptors, AMPA |2 NLM | |
| 700 | 1 | |a De Luca, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Lever, Michael B |e verfasserin |4 aut | |
| 700 | 1 | |a Richner, Mette |e verfasserin |4 aut | |
| 700 | 1 | |a Hansen, Astrid B |e verfasserin |4 aut | |
| 700 | 1 | |a Noes-Holt, Gith |e verfasserin |4 aut | |
| 700 | 1 | |a Jensen, Kathrine L |e verfasserin |4 aut | |
| 700 | 1 | |a Rathje, Mette |e verfasserin |4 aut | |
| 700 | 1 | |a Jensen, Dennis Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Erlendsson, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Bartling, Christian Ro |e verfasserin |4 aut | |
| 700 | 1 | |a Ammendrup-Johnsen, Ina |e verfasserin |4 aut | |
| 700 | 1 | |a Pedersen, Sofie E |e verfasserin |4 aut | |
| 700 | 1 | |a Schönauer, Michèle |e verfasserin |4 aut | |
| 700 | 1 | |a Nissen, Klaus B |e verfasserin |4 aut | |
| 700 | 1 | |a Midtgaard, Søren R |e verfasserin |4 aut | |
| 700 | 1 | |a Teilum, Kaare |e verfasserin |4 aut | |
| 700 | 1 | |a Arleth, Lise |e verfasserin |4 aut | |
| 700 | 1 | |a Sørensen, Andreas T |e verfasserin |4 aut | |
| 700 | 1 | |a Bach, Anders |e verfasserin |4 aut | |
| 700 | 1 | |a Strømgaard, Kristian |e verfasserin |4 aut | |
| 700 | 1 | |a Meehan, Claire F |e verfasserin |4 aut | |
| 700 | 1 | |a Vaegter, Christian B |e verfasserin |4 aut | |
| 700 | 1 | |a Gether, Ulrik |e verfasserin |4 aut | |
| 700 | 1 | |a Madsen, Kenneth L |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t EMBO molecular medicine |d 2009 |g 12(2020), 6 vom: 08. Juni, Seite e11248 |w (DE-627)NLM192618962 |x 1757-4684 |7 nnns |
| 773 | 1 | 8 | |g volume:12 |g year:2020 |g number:6 |g day:08 |g month:06 |g pages:e11248 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.15252/emmm.201911248 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 12 |j 2020 |e 6 |b 08 |c 06 |h e11248 | ||