Spinophilin regulates phosphorylation and interactions of the GluN2B subunit of the N-methyl-d-aspartate receptor.

Autor: Salek AB; Department of Biology, Indiana University-Purdue University, Indianapolis, Indiana, USA., Edler MC; Department of Biology, Indiana University-Purdue University, Indianapolis, Indiana, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA., McBride JP; Department of Biology, Indiana University-Purdue University, Indianapolis, Indiana, USA., Baucum AJ 2nd; Department of Biology, Indiana University-Purdue University, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2019 Oct; Vol. 151 (2), pp. 185-203. Date of Electronic Publication: 2019 Aug 02.
DOI: 10.1111/jnc.14831
Abstrakt: N-methyl-d-Aspartate receptors (NMDARs) are abundant postsynaptic proteins that are critical for normal synaptic communication. NMDAR channel function is regulated by multiple properties, including phosphorylation. Inhibition of protein phosphatase 1 (PP1) in hippocampal neurons increases NMDAR activity, an effect abrogated by loss of spinophilin, the major PP1-targeting protein in the postsynaptic density. However, how spinophilin regulates PP1-dependent NMDAR function is unclear. We hypothesize that spinophilin regulates PP1 binding to the NMDAR to alter NMDAR phosphorylation. Our data demonstrate that spinophilin interacts with the GluN2B subunit of the NMDAR. In human embryonic kidney 293 FT cells, activation and/or overexpression of protein kinase A increased the association between spinophilin and the GluN2B subunit of the NMDAR. Functionally, we found that spinophilin overexpression decreased PP1 binding to the GluN2B subunit of the NMDAR and attenuated the PP1-dependent dephosphorylation of GluN2B at Ser-1284. Moreover, in P28 hippocampal lysates isolated from spinophilin KO compared to WT mice, there was increased binding of GluN2B to PP1, decreased phosphorylation of GluN2B at Ser-1284, and altered GluN2B protein interactions with postsynaptic density-enriched proteins. Together, our data demonstrate that spinophilin decreases PP1 binding to GluN2B and concomitantly enhances the phosphorylation of GluN2B at Ser-1284. The putative consequences of these spinophilin-dependent alterations in GluN2B phosphorylation and interactions on synaptic GluN2B localization and function are discussed. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.
(© 2019 International Society for Neurochemistry.)
Databáze: MEDLINE
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