Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction

Edward Y.S. Lin; Laura F. Silvian; Douglas J. Marcotte; Charles C. Banos; Flora Jow; Timothy R. Chan; Robert M. Arduini; Fang Qian; Darren P. Baker; Chris Bergeron; Catherine A. Hession; Richard L. Huganir; Cassandra F. Borenstein; Istvan Enyedy; Jinming Zou; Ellen Rohde; Marion Wittmann; Gnanasambandam Kumaravel; Kenneth J. Rhodes; Robert H. Scannevin; Anthone W. Dunah; Kevin M. Guckian

doi:10.1038/s41598-018-31680-3

Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction

Edward Y.S. Lin, Laura F. Silvian, Douglas J. Marcotte, Charles C. Banos, Flora Jow, Timothy R. Chan, Robert M. Arduini, Fang Qian, Darren P. Baker, Chris Bergeron, Catherine A. Hession, Richard L. Huganir, Cassandra F. Borenstein, Istvan Enyedy, Jinming Zou, Ellen Rohde, Marion Wittmann, Gnanasambandam Kumaravel, Kenneth J. Rhodes, Robert H. ScannevinAnthone W. Dunah, Kevin M. Guckian

School of Medicine

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Abstract

Protein interacting with C kinase (PICK1) is a scaffolding protein that is present in dendritic spines and interacts with a wide array of proteins through its PDZ domain. The best understood function of PICK1 is regulation of trafficking of AMPA receptors at neuronal synapses via its specific interaction with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 interaction has been shown to alter synaptic plasticity, a molecular mechanism of learning and memory. Lack of potent, selective inhibitors of the PICK1 PDZ domain has hindered efforts at exploring the PICK1-GluA2 interaction as a therapeutic target for neurological diseases. Here, we report the discovery of PICK1 small molecule inhibitors using a structure-based drug design strategy. The inhibitors stabilized surface GluA2, reduced Aβ-induced rise in intracellular calcium concentrations in cultured neurons, and blocked long term depression in brain slices. These findings demonstrate that it is possible to identify potent, selective PICK1-GluA2 inhibitors which may prove useful for treatment of neurodegenerative disorders.

Original language	English (US)
Article number	13438
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-31680-3
State	Published - Dec 1 2018

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Lin, E. Y. S., Silvian, L. F., Marcotte, D. J., Banos, C. C., Jow, F., Chan, T. R., Arduini, R. M., Qian, F., Baker, D. P., Bergeron, C., Hession, C. A., Huganir, R. L., Borenstein, C. F., Enyedy, I., Zou, J., Rohde, E., Wittmann, M., Kumaravel, G., Rhodes, K. J., ... Guckian, K. M. (2018). Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction. Scientific reports, 8(1), Article 13438. https://doi.org/10.1038/s41598-018-31680-3

Lin, EYS, Silvian, LF, Marcotte, DJ, Banos, CC, Jow, F, Chan, TR, Arduini, RM, Qian, F, Baker, DP, Bergeron, C, Hession, CA, Huganir, RL, Borenstein, CF, Enyedy, I, Zou, J, Rohde, E, Wittmann, M, Kumaravel, G, Rhodes, KJ, Scannevin, RH, Dunah, AW & Guckian, KM 2018, 'Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction', Scientific reports, vol. 8, no. 1, 13438. https://doi.org/10.1038/s41598-018-31680-3

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title = "Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction",

abstract = "Protein interacting with C kinase (PICK1) is a scaffolding protein that is present in dendritic spines and interacts with a wide array of proteins through its PDZ domain. The best understood function of PICK1 is regulation of trafficking of AMPA receptors at neuronal synapses via its specific interaction with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 interaction has been shown to alter synaptic plasticity, a molecular mechanism of learning and memory. Lack of potent, selective inhibitors of the PICK1 PDZ domain has hindered efforts at exploring the PICK1-GluA2 interaction as a therapeutic target for neurological diseases. Here, we report the discovery of PICK1 small molecule inhibitors using a structure-based drug design strategy. The inhibitors stabilized surface GluA2, reduced Aβ-induced rise in intracellular calcium concentrations in cultured neurons, and blocked long term depression in brain slices. These findings demonstrate that it is possible to identify potent, selective PICK1-GluA2 inhibitors which may prove useful for treatment of neurodegenerative disorders.",

author = "Lin, {Edward Y.S.} and Silvian, {Laura F.} and Marcotte, {Douglas J.} and Banos, {Charles C.} and Flora Jow and Chan, {Timothy R.} and Arduini, {Robert M.} and Fang Qian and Baker, {Darren P.} and Chris Bergeron and Hession, {Catherine A.} and Huganir, {Richard L.} and Borenstein, {Cassandra F.} and Istvan Enyedy and Jinming Zou and Ellen Rohde and Marion Wittmann and Gnanasambandam Kumaravel and Rhodes, {Kenneth J.} and Scannevin, {Robert H.} and Dunah, {Anthone W.} and Guckian, {Kevin M.}",

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AU - Banos, Charles C.

AU - Jow, Flora

AU - Chan, Timothy R.

AU - Arduini, Robert M.

AU - Qian, Fang

AU - Baker, Darren P.

AU - Bergeron, Chris

AU - Hession, Catherine A.

AU - Huganir, Richard L.

AU - Borenstein, Cassandra F.

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AU - Zou, Jinming

AU - Rohde, Ellen

AU - Wittmann, Marion

AU - Kumaravel, Gnanasambandam

AU - Rhodes, Kenneth J.

AU - Scannevin, Robert H.

AU - Dunah, Anthone W.

AU - Guckian, Kevin M.

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N2 - Protein interacting with C kinase (PICK1) is a scaffolding protein that is present in dendritic spines and interacts with a wide array of proteins through its PDZ domain. The best understood function of PICK1 is regulation of trafficking of AMPA receptors at neuronal synapses via its specific interaction with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 interaction has been shown to alter synaptic plasticity, a molecular mechanism of learning and memory. Lack of potent, selective inhibitors of the PICK1 PDZ domain has hindered efforts at exploring the PICK1-GluA2 interaction as a therapeutic target for neurological diseases. Here, we report the discovery of PICK1 small molecule inhibitors using a structure-based drug design strategy. The inhibitors stabilized surface GluA2, reduced Aβ-induced rise in intracellular calcium concentrations in cultured neurons, and blocked long term depression in brain slices. These findings demonstrate that it is possible to identify potent, selective PICK1-GluA2 inhibitors which may prove useful for treatment of neurodegenerative disorders.

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Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction

Abstract

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