Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

被引：97

作者：

Thorsen, Thor S. ^{[1
,2
]}

Madsen, Kenneth L. ^{[1
,2
]}

Rebola, Nelson ^{[3
]}

Rathje, Mette ^{[1
,2
]}

Anggono, Victor ^{[4
]}

Bach, Anders ^{[5
]}

Moreira, Irina S. ^{[6
]}

Stuhr-Hansen, Nicolai ^{[5
]}

Dyhring, Tino ^{[7
]}

Peters, Dan ^{[7
]}

Beuming, Thijs ^{[6
]}

Huganir, Richard ^{[4
]}

Weinstein, Harel ^{[6
]}

Mulle, Christophe ^{[3
]}

Stromgaard, Kristian ^{[5
]}

Ronn, Lars Christian B. ^{[7
]}

Gether, Ulrik ^{[1
,2
]}

机构：

[1] Univ Copenhagen, Mol Neuropharmacol Grp, DK-2200 Copenhagen, Denmark

[2] Univ Copenhagen, Ctr Pharmacogenom, Dept Neurosci & Pharmacol, Panum Inst, DK-2200 Copenhagen, Denmark

[3] Univ Bordeaux, Lab Physiol Cellulaire Synapse, CNRS UMR 5091, Bordeaux Neurosci Inst, F-33077 Bordeaux, France

[4] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Neurosci, Baltimore, MD 21205 USA

[5] Univ Copenhagen, Fac Pharmaceut Sci, Dept Med Chem, DK-2100 Copenhagen, Denmark

[6] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA

[7] Neurosearch AS, Drug Discovery, DK-2750 Ballerup, Denmark

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 01期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

drug discovery; fluorescence polarization; protein-protein interactions; synaptic plasticity; AMPA receptors; LONG-TERM DEPRESSION; PROTEIN-PROTEIN INTERACTIONS; RECEPTOR SUBUNIT GLUR2; SYNAPTIC PLASTICITY; AMPA RECEPTORS; IN-VIVO; PHOSPHORYLATION; TRANSPORTER; SPECIFICITY; MUTATIONS;

D O I：

10.1073/pnas.0902225107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) domains play key roles in the assembly and regulation of cellular signaling pathways and represent putative targets for new pharmacotherapeutics. Here we describe the first small-molecule inhibitor (FSC231) of the PDZ domain in protein interacting with C kinase 1(PICK1) identified by a screening of similar to 44,000 compounds in a fluorescent polarization assay. The inhibitor bound the PICK1 PDZ domain with an affinity similar to that observed for endogenous peptide ligands (K-i similar to 10.1 mu M). Mutational analysis, together with computational docking of the compound in simulations starting from the PDZ domain structure, identified the binding mode of FSC231. The specificity of FSC231 for the PICK1 PDZ domain was supported by the lack of binding to PDZ domains of postsynaptic density protein 95 (PSD-95) and glutamate receptor interacting protein 1 (GRIP1). Pretreatment of cultured hippocampal neurons with FSC231 inhibited coimmunopreciptation of the AMPA receptor GluR2 subunit with PICK1. In agreement with inhibiting the role of PICK1 in GluR2 trafficking, FSC231 accelerated recycling of pHluorin-tagged GluR2 in hippocampal neurons after internalization in response to NMDA receptor-activation. FSC231 blocked the expression of both long-term depression and long-term potentiation in hippocampal CA1 neurons from acute slices, consistent with inhibition of the bidirectional function of PICK1 in synaptic plasticity. Given the proposed role of the PICK1/AMPA receptor interaction in neuropathic pain, excitotoxicity, and cocaine addiction, FSC231 might serve as a lead in the future development of new therapeutics against these conditions.

引用

页码：413 / 418

页数：6

共 41 条

[1] Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions [J].