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

Research output: Contribution to journalJournal articlepeer-review

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A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain. / Christensen, Nikolaj R.; De Luca, Marta; Lever, Michael B.; Richner, Mette; Hansen, Astrid B.; Noes-Holt, Gith; Jensen, Kathrine L.; Rathje, Mette; Jensen, Dennis Bo; Erlendsson, Simon; Bartling, Christian R.O.; Ammendrup-Johnsen, Ina; Pedersen, Sofie E.; Schönauer, Michèle; Nissen, Klaus B.; Midtgaard, Søren R.; Teilum, Kaare; Arleth, Lise; Sørensen, Andreas T.; Bach, Anders; Strømgaard, Kristian; Meehan, Claire F.; Vægter, Christian B.; Gether, Ulrik; Madsen, Kenneth L.

In: EMBO Molecular Medicine, Vol. 12, No. 6, e11248, 2020.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Christensen, NR, De Luca, M, Lever, MB, Richner, M, Hansen, AB, Noes-Holt, G, Jensen, KL, Rathje, M, Jensen, DB, Erlendsson, S, Bartling, CRO, Ammendrup-Johnsen, I, Pedersen, SE, Schönauer, M, Nissen, KB, Midtgaard, SR, Teilum, K, Arleth, L, Sørensen, AT, Bach, A, Strømgaard, K, Meehan, CF, Vægter, CB, Gether, U & Madsen, KL 2020, 'A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain', EMBO Molecular Medicine, vol. 12, no. 6, e11248. https://doi.org/10.15252/emmm.201911248

APA

Christensen, N. R., De Luca, M., Lever, M. B., Richner, M., Hansen, A. B., Noes-Holt, G., Jensen, K. L., Rathje, M., Jensen, D. B., Erlendsson, S., Bartling, C. R. O., Ammendrup-Johnsen, I., Pedersen, S. E., Schönauer, M., Nissen, K. B., Midtgaard, S. R., Teilum, K., Arleth, L., Sørensen, A. T., ... Madsen, K. L. (2020). A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain. EMBO Molecular Medicine, 12(6), [e11248]. https://doi.org/10.15252/emmm.201911248

Vancouver

Christensen NR, De Luca M, Lever MB, Richner M, Hansen AB, Noes-Holt G et al. A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain. EMBO Molecular Medicine. 2020;12(6). e11248. https://doi.org/10.15252/emmm.201911248

Author

Christensen, Nikolaj R. ; De Luca, Marta ; Lever, Michael B. ; Richner, Mette ; Hansen, Astrid B. ; Noes-Holt, Gith ; Jensen, Kathrine L. ; Rathje, Mette ; Jensen, Dennis Bo ; Erlendsson, Simon ; Bartling, Christian R.O. ; Ammendrup-Johnsen, Ina ; Pedersen, Sofie E. ; Schönauer, Michèle ; Nissen, Klaus B. ; Midtgaard, Søren R. ; Teilum, Kaare ; Arleth, Lise ; Sørensen, Andreas T. ; Bach, Anders ; Strømgaard, Kristian ; Meehan, Claire F. ; Vægter, Christian B. ; Gether, Ulrik ; Madsen, Kenneth L. / A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain. In: EMBO Molecular Medicine. 2020 ; Vol. 12, No. 6.

Bibtex

@article{be3d9f21e7d44ae8955c071a249267b3,
title = "A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain",
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",
author = "Christensen, {Nikolaj R.} and {De Luca}, Marta and Lever, {Michael B.} and Mette Richner and Hansen, {Astrid B.} and Gith Noes-Holt and Jensen, {Kathrine L.} and Mette Rathje and Jensen, {Dennis Bo} and Simon Erlendsson and Bartling, {Christian R.O.} and Ina Ammendrup-Johnsen and Pedersen, {Sofie E.} and Mich{\`e}le Sch{\"o}nauer and Nissen, {Klaus B.} and Midtgaard, {S{\o}ren R.} and Kaare Teilum and Lise Arleth and S{\o}rensen, {Andreas T.} and Anders Bach and Kristian Str{\o}mgaard and Meehan, {Claire F.} and V{\ae}gter, {Christian B.} and Ulrik Gether and Madsen, {Kenneth L.}",
year = "2020",
doi = "10.15252/emmm.201911248",
language = "English",
volume = "12",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "6",

}

RIS

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 -

ID: 241044663