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NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR-Plasticity

42 Pages Posted: 7 Feb 2019 Sneak Peek Status: Published

See all articles by Andrew M. Chiu

Andrew M. Chiu

Northwestern University - Department of Pharmacology

Jiejie Wang

Northwestern University - Department of Pharmacology; University of California, San Francisco (UCSF) - Department of Neurology

Michael P. Fiske

Northwestern University - Department of Physiology

Pavla Hubalkova

Northwestern University - Department of Pharmacology; Institute of Physiology CAS - Department of Cellular Neurophysiology

Levi Barse

Northwestern University - Department of Pharmacology

John A. Gray

University of California, Davis - Department of Neurology

Antonio Sanz-Clemente

Northwestern University - Department of Pharmacology

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Abstract

In mature neurons, postsynaptic NMDARs are segregated into two populations, synaptic and extrasynaptic NMDARs, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content (NMDAR-plasticity). Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR subsynaptic localization. We find that this phosphorylation maintains NMDARs segregated at extrasynaptic membranes as part of a protein complex containing inactive Protein Phosphatase 1 (PP1). Global activation of NMDARs lead to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates activity-dependent NMDAR-plasticity in mature neurons, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission.

Suggested Citation

Chiu, Andrew M. and Wang, Jiejie and Fiske, Michael P. and Hubalkova, Pavla and Barse, Levi and Gray, John A. and Sanz-Clemente, Antonio, NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR-Plasticity (February 7, 2019). Available at SSRN: https://ssrn.com/abstract=3330559 or http://dx.doi.org/10.2139/ssrn.3330559
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Andrew M. Chiu

Northwestern University - Department of Pharmacology

Chicago, IL 60611
United States

Jiejie Wang

Northwestern University - Department of Pharmacology

Chicago, IL 60611
United States

University of California, San Francisco (UCSF) - Department of Neurology

San Francisco, CA
United States

Michael P. Fiske

Northwestern University - Department of Physiology

2001 Sheridan Road
Evanston, IL 60208
United States

Pavla Hubalkova

Northwestern University - Department of Pharmacology

Chicago, IL 60611
United States

Institute of Physiology CAS - Department of Cellular Neurophysiology

Prague
Czech Republic

Levi Barse

Northwestern University - Department of Pharmacology

Chicago, IL 60611
United States

John A. Gray

University of California, Davis - Department of Neurology

Davis, CA
United States

Antonio Sanz-Clemente (Contact Author)

Northwestern University - Department of Pharmacology ( email )

Chicago, IL 60611
United States

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