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

T. S. Thorsen, K. L. Madsen, N. Rebola, M. Rathje, V. Anggono, A. Bach, I. S. Moreira, N. Stuhr-Hansen, T. Dyhring, D. Peters, T. Beuming, R. Huganir, H. Weinstein, C. Mulle, K. Stromgaard, L. C. B. Ronn, U. Gether
Proceedings of the National Academy of Sciences. 2009-12-14; 107(1): 413-418
DOI: 10.1073/pnas.0902225107

Lire sur PubMed

1. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):413-8. doi: 10.1073/pnas.0902225107.
Epub 2009 Dec 14.

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

Thorsen TS(1), Madsen KL, Rebola N, Rathje M, Anggono V, Bach A, Moreira IS,
Stuhr-Hansen N, Dyhring T, Peters D, Beuming T, Huganir R, Weinstein H, Mulle C,
Strømgaard K, Rønn LC, Gether U.

Author information:
(1)Molecular Neuropharmacology Group and Center for Pharmacogenomics, Department
of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen,
DK-2200 Copenhagen, Denmark.

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 approximately 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)
approximately 10.1 microM). 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

DOI: 10.1073/pnas.0902225107
PMCID: PMC2806717
PMID: 20018661 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus