A novel phosphorylation site of N-methyl- d -aspartate receptor GluN2B at S1284 is regulated by Cdk5 in neuronal ischemia

Lu, W. T.; Ai, Hui; Peng, Lin; Wang, Jiejie; Zhang, Bin; Liu, Xiao; Luo, Jianhong

doi:10.1016/j.expneurol.2015.06.016

Cited by 23 publications

(19 citation statements)

References 45 publications

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“…5e; GluN2B Tail (20.39 AE 0.2537%) versus GluN2B Tail + PP1 (3.447 AE 0.2049%), ****p < 0.0001). Overexpression of PKA alone or along with PP1c1 did not increase Ser-1284 phosphorylation, suggesting that this is not a PKA sensitive site, consistent with other data suggesting it is a cyclin-dependent kinase 5 site (Lu et al 2015). Co-expression of spinophilin along with PKA and PP1c1 attenuated the PP1dependent decrease in Ser-1284 phosphorylation ( Fig.…”

Section: Spinophilin Rescues Pp1-dependent Dephosphorylation Of Ser-1supporting

confidence: 89%

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

Salek

Edler

McBride

et al. 2019

Journal of Neurochemistry

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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/

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Section: Spinophilin Rescues Pp1-dependent Dephosphorylation Of Ser-1supporting

confidence: 89%

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

Salek

Edler

McBride

et al. 2019

Journal of Neurochemistry

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“…PSD fractionation was conducted on adult rat hippocampus using an adapted protocol (Pacchioni et al, 2009; Lu et al, 2015a). …”

Section: Methodsmentioning

confidence: 99%

“…A biotinylation assay was performed as reported previously (Cao et al, 2007; Lu et al, 2015a; Zhang et al, 2015). In general, high density cultured hippocampal neurons at DIV13–15 were rinsed twice with buffer A (1× PBS with 0.5 mM MgCl 2 and 1 mM CaCl 2 ).…”

Section: Methodsmentioning

confidence: 99%

Huntingtin-Interacting Protein 1-Related Protein Plays a Critical Role in Dendritic Development and Excitatory Synapse Formation in Hippocampal Neurons

Peng

Yang

et al. 2017

Front. Mol. Neurosci.

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Huntingtin-interacting protein 1-related (HIP1R) protein is considered to be an endocytic adaptor protein like the other two members of the Sla2 family, Sla2p and HIP1. They all contain homology domains responsible for the binding of clathrin, inositol lipids and F-actin. Previous studies have revealed that HIP1R is highly expressed in different regions of the mouse brain and localizes at synaptic structures. However, the function of HIP1R in the nervous system remains unknown. In this study, we investigated HIP1R function in cultured rat hippocampal neurons using an shRNA knockdown approach. We found that, after HIP1R knockdown, the dynamics and density of dendritic filopodia, and dendritic branching and complexity were significantly reduced in developing neurons, as well as the densities of dendritic spines and PSD95 clusters in mature neurons. Moreover, HIP1R deficiency led to significantly reduced expression of the ionotropic glutamate receptor GluA1, GluN2A and GluN2B subunits, but not the GABAA receptor α1 subunit. Similarly, HIP1R knockdown reduced the amplitude and frequency of the miniature excitatory postsynaptic current, but not of the miniature inhibitory postsynaptic current. In addition, the C-terminal proline-rich region of HIP1R responsible for cortactin binding was found to confer a dominant-negative effect on dendritic branching in cultured developing neurons, implying a critical role of cortactin binding in HIP1R function. Taken together, the results of our study suggest that HIP1R plays important roles in dendritic development and excitatory synapse formation and function.

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“…Western blot was performed according to our previous protocol [31,35]. Briefly, equal amounts of protein (20μg) were loaded onto 10% SDS-PAGE and then transferred to nitrocellulose membranes (Protran BA 85, Whatman, GE).…”

Section: Western Blotmentioning

confidence: 99%

Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase

Ai¹,

Fang²,

Hu³

et al. 2020

Aging and disease

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Depression is one of the most prevalent neuropsychiatric disorders in modern society. However, traditional drugs, such as monoaminergic agents, have defect showing lag response requiring several weeks to months. Additionally, these drugs have limited efficacy and high resistance rates in patients with depression. Thus, there is an urgent need to develop novel drugs or approaches for the treatment of depression. Here, using biochemical, pharmacological, genetic and behavioral methods, we demonstrate that metformin imparts a fastacting antidepressant-like effect in naï ve mice as well as stressed mice subjected to chronic restraint stress model. Moreover, inhibition of AMP-activated protein kinase (AMPK) activity by compound C or knock down of hippocampal AMPKα occluded the antidepressant-like effect induced by metformin. Our results suggest that metformin may be a viable therapeutic drug for the treatment of stress-induced depression via activation of AMPK.

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A novel phosphorylation site of N-methyl- d -aspartate receptor GluN2B at S1284 is regulated by Cdk5 in neuronal ischemia

Cited by 23 publications

References 45 publications

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

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

Huntingtin-Interacting Protein 1-Related Protein Plays a Critical Role in Dendritic Development and Excitatory Synapse Formation in Hippocampal Neurons

Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase

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