Browse
Submit Data
Databases
API
Help

Dataset Information

30 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK.

ABSTRACT: Jun N-terminal kinases (JNKs) are implicated in various neuropathological conditions. However, physiological roles for JNKs in neurons remain largely unknown, despite the high expression level of JNKs in brain. Here, using bioinformatic and biochemical approaches, we identify the AMPA receptor GluR2L and GluR4 subunits as novel physiological JNK substrates in vitro, in heterologous cells and in neurons. Consistent with this finding, GluR2L and GluR4 associate with specific JNK signaling components in the brain. Moreover, the modulation of the novel JNK sites in GluR2L and GluR4 is dynamic and bi-directional, such that phosphorylation and de-phosphorylation are triggered within minutes following decreases and increases in neuronal activity, respectively. Using live-imaging techniques to address the functional consequence of these activity-dependent changes we demonstrate that the novel JNK site in GluR2L controls reinsertion of internalized GluR2L back to the cell surface following NMDA treatment, without affecting basal GluR2L trafficking. Taken together, our results demonstrate that JNK directly regulates AMPA-R trafficking following changes in neuronal activity in a rapid and bi-directional manner.

SUBMITTER: Thomas GM

PROVIDER: S-EPMC2196436 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

SynDIG1 promotes excitatory synaptogenesis independent of AMPA receptor trafficking and biophysical regulation.

Project description:AMPA receptors-mediators of fast, excitatory transmission and synaptic plasticity in the brain-achieve great functional diversity through interaction with different auxiliary subunits, which alter both the trafficking and biophysical properties of these receptors. In the past several years an abundance of new AMPA receptor auxiliary subunits have been identified, adding astounding variety to the proteins known to directly bind and modulate AMPA receptors. SynDIG1 was recently identified as a novel AMPA receptor interacting protein that directly binds to the AMPA receptor subunit GluA2 in heterologous cells. Functionally, SynDIG1 was found to regulate the strength and density of AMPA receptor containing synapses in hippocampal neurons, though the way in which SynDIG1 exerts these effects remains unknown. Here, we aimed to determine if SynDIG1 acts as a traditional auxiliary subunit, directly regulating the function and localization of AMPA receptors in the rat hippocampus. We find that, unlike any of the previously characterized AMPA receptor auxiliary subunits, SynDIG1 expression does not impact AMPA receptor gating, pharmacology, or surface trafficking. Rather, we show that SynDIG1 regulates the number of functional excitatory synapses, altering both AMPA and NMDA receptor mediated transmission. Our findings suggest that SynDIG1 is not a typical auxiliary subunit to AMPA receptors, but instead is a protein critical to excitatory synaptogenesis.

| S-EPMC3681968 | biostudies-literature

Regulation of AMPA receptor trafficking and function by glycogen synthase kinase 3.

Project description:Accumulating evidence suggests that glycogen synthase kinase 3 (GSK-3) is a multifunctional kinase implicated in neuronal development, mood stabilization, and neurodegeneration. However, the synaptic actions of GSK-3 are largely unknown. In this study, we examined the impact of GSK-3 on AMPA receptor (AMPAR) channels, the major mediator of excitatory transmission, in cortical neurons. Application of GSK-3 inhibitors or knockdown of GSK-3 caused a significant reduction of the amplitude of miniature excitatory postsynaptic current (mEPSC), a readout of the unitary strength of synaptic AMPARs. Treatment with GSK-3 inhibitors also decreased surface and synaptic GluR1 clusters on dendrites and increased internalized GluR1 in cortical cultures. Rab5, the small GTPase controlling the transport from plasma membrane to early endosomes, was activated by GSK-3 inhibitors. Knockdown of Rab5 prevented GSK-3 inhibitors from regulating mEPSC amplitude. Guanyl nucleotide dissociation inhibitor (GDI), which regulates the cycle of Rab5 between membrane and cytosol, formed an increased complex with Rab5 after treatment with GSK-3 inhibitors. Blocking the function of GDI occluded the effect of GSK-3 inhibitors on mEPSC amplitude. In cells transfected with the non-phosphorylatable GDI mutant, GDI(S45A), GSK-3 inhibitors lost the capability to regulate GDI-Rab5 complex, mEPSC amplitude, and AMPAR surface expression. These results suggest that GSK-3, via altering the GDI-Rab5 complex, regulates Rab5-mediated endocytosis of AMPARs. It provides a potential mechanism underlying the role of GSK-3 in synaptic transmission and plasticity.

| S-EPMC2924064 | biostudies-literature

Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation.

Project description:The insertion of AMPA receptors (AMPARs) into the plasma membrane is an important step in the synaptic delivery of AMPARs during the expression of synaptic plasticity. However, the molecular mechanisms regulating AMPAR insertion remain elusive. By directly visualizing individual insertion events of the AMPAR subunit GluR1 in rodents, we found that the protein 4.1N was required for activity-dependent GluR1 insertion. Protein kinase C (PKC) phosphorylation of the serine 816 (S816) and S818 residues of GluR1 enhanced 4.1N binding to GluR1 and facilitated GluR1 insertion. In addition, palmitoylation of GluR1 C811 residue modulated PKC phosphorylation and GluR1 insertion. Finally, disrupting 4.1N-dependent GluR1 insertion decreased surface expression of GluR1 and the expression of long-term potentiation. Our study uncovers a previously unknown mechanism that governs activity-dependent GluR1 trafficking, reveals an interaction between AMPAR palmitoylation and phosphorylation, and underscores the functional importance of 4.1N in AMPAR trafficking and synaptic plasticity.

| S-EPMC2712131 | biostudies-literature

Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation.

Project description:During homeostatic adjustment in response to alterations in neuronal activity, synaptic expression of AMPA receptors (AMPARs) is globally tuned up or down so that the neuronal activity is restored to a physiological range. Given that a central neuron receives multiple presynaptic inputs, whether and how AMPAR synaptic expression is homeostatically regulated at individual synapses remain unclear. In cultured hippocampal neurons we report that when activity of an individual presynaptic terminal is selectively elevated by light-controlled excitation, AMPAR abundance at the excited synapses is selectively downregulated in an NMDAR-dependent manner. The reduction in surface AMPARs is accompanied by enhanced receptor endocytosis and dependent on proteasomal activity. Synaptic activation also leads to a site-specific increase in the ubiquitin ligase Nedd4 and polyubiquitination levels, consistent with AMPAR ubiquitination and degradation in the spine. These results indicate that AMPAR accumulation at individual synapses is subject to autonomous homeostatic regulation in response to synaptic activity.

| S-EPMC3240854 | biostudies-literature

Adenosine A1 and dopamine d1 receptor regulation of AMPA receptor phosphorylation and cocaine-seeking behavior.

Project description:AMPAR (?-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptor) stimulation in the nucleus accumbens (NAc) is critical in cocaine seeking. Here, we investigate the functional interaction between D1 dopamine receptors (D1DR) and AMPARs in the NAc, and explore how A1 adenosine receptor (A1AR) stimulation may reduce dopamine-induced facilitation of AMPARs and cocaine seeking. All animals were trained to self-administer cocaine and were tested for reinstatement of cocaine seeking following extinction procedures. The role of AMPARs in both AMPA- and D1DR-induced cocaine seeking was assessed using viral-mediated gene transfer to bi-directionally modulate AMPAR activity in the NAc core. The ability of pharmacological AMPAR blockade to modulate D1DR-induced cocaine seeking also was tested. Immunoblotting was used to determine whether stimulating D1DR altered synaptic AMPA GluA1 phosphorylation (pGluA1). Finally, the ability of an A1AR agonist to modulate D1DR-induced cocaine seeking and synaptic GluA1 receptor subunit phosphorylation was explored. Decreasing AMPAR function inhibited both AMPA- and D1DR-induced cocaine seeking. D1DR stimulation increased AMPA pGluA1(S845). Administration of the A1AR agonist alone decreased synaptic GluA1 expression, whereas coadministration of the A1AR agonist inhibited both cocaine- and D1DR-induced cocaine seeking and reversed D1DR-induced AMPA pGluA1(S845). These findings suggest that D1DR stimulation facilitates AMPAR function to initiate cocaine seeking in D1DR-containing direct pathway NAc neurons. A1AR stimulation inhibits both the facilitation of AMPAR function and subsequent cocaine seeking, suggesting that reducing AMPA glutamate neurotransmission in direct pathway neurons may restore inhibitory control and reduce cocaine relapse.

| S-EPMC3746705 | biostudies-literature

Dynamic bi-directional phosphorylation events associated with the reciprocal regulation of synapses during homeostatic up- and down-scaling.

Project description:Homeostatic synaptic scaling allows for bi-directional adjustment of the strength of synaptic connections in response to changes in their input. Protein phosphorylation modulates many neuronal processes, but it has not been studied on a global scale during synaptic scaling. Here, we use liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses to measure changes in the phosphoproteome in response to up- or down-scaling in cultured cortical neurons over minutes to 24 h. Of ~45,000 phosphorylation events, ~3,300 (associated with 1,285 phosphoproteins) are regulated by homeostatic scaling. Activity-sensitive phosphoproteins are predominantly located at synapses and involved in cytoskeletal reorganization. We identify many early phosphorylation events that could serve as sensors for the activity offset as well as late and/or persistent phosphoregulation that could represent effector mechanisms driving the homeostatic response. Much of the persistent phosphorylation is reciprocally regulated by up- or down-scaling, suggesting that mechanisms underlying these two poles of synaptic regulation make use of a common signaling axis.

| S-EPMC8411114 | biostudies-literature

A GluR1-cGKII interaction regulates AMPA receptor trafficking.

Project description:Trafficking of AMPA receptors (AMPARs) is regulated by specific interactions of the subunit intracellular C-terminal domains (CTDs) with other proteins, but the mechanisms involved in this process are still unclear. We have found that the GluR1 CTD binds to cGMP-dependent protein kinase II (cGKII) adjacent to the kinase catalytic site. Binding of GluR1 is increased when cGKII is activated by cGMP. cGKII and GluR1 form a complex in the brain, and cGKII in this complex phosphorylates GluR1 at S845, a site also phosphorylated by PKA. Activation of cGKII by cGMP increases the surface expression of AMPARs at extrasynaptic sites. Inhibition of cGKII activity blocks the surface increase of GluR1 during chemLTP and reduces LTP in the hippocampal slice. This work identifies a pathway, downstream from the NMDA receptor (NMDAR) and nitric oxide (NO), which stimulates GluR1 accumulation in the plasma membrane and plays an important role in synaptic plasticity.

| S-EPMC2153457 | biostudies-literature

PACSIN1 regulates the dynamics of AMPA receptor trafficking.

Project description:Dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses plays an important role in synaptic plasticity. We previously reported that the protein kinase C and casein kinase II substrate in neurons (PACSIN) forms a complex with AMPARs through its interaction with the protein interacting with C-kinase 1 (PICK1) to regulate NMDA receptor (NMDAR)-induced AMPAR endocytosis and cerebellar long-term depression. However, the molecular mechanism by which PACSIN regulates the dynamics of AMPAR trafficking remains unclear. Using a pH-sensitive green fluorescent protein, pHluorin, tagged to the extracellular domain of the GluA2 subunit of AMPARs, we demonstrate dual roles for PACSIN1 in controlling the internalization and recycling of GluA2 after NMDAR activation. Structure and function analysis reveals a requirement for the PACSIN1 F-BAR and SH3 domains in controlling these NMDAR-dependent processes. Interestingly, the variable region, which binds to PICK1, is not essential for NMDAR-dependent GluA2 internalization and is required only for the correct recycling of AMPARs. These results indicate that PACSIN is a versatile membrane deformation protein that links the endocytic and recycling machineries essential for dynamic AMPAR trafficking in neurons.

| S-EPMC4973260 | biostudies-literature

Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking.

Project description:?-Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) are the primary mediators of excitatory synaptic transmission in the brain. Alterations in AMPAR localization and turnover have been considered critical mechanisms underpinning synaptic plasticity and higher brain functions, but the molecular processes that control AMPAR trafficking and stability are still not fully understood. Here, we report that mammalian AMPARs are subject to ubiquitination in neurons and in transfected heterologous cells. Ubiquitination facilitates AMPAR endocytosis, leading to a reduction in AMPAR cell-surface localization and total receptor abundance. Mutation of lysine residues to arginine residues at the glutamate receptor subunit 1 (GluA1) C-terminus dramatically reduces GluA1 ubiquitination and abolishes ubiquitin-dependent GluA1 internalization and degradation, indicating that the lysine residues, particularly K868, are sites of ubiquitination. We also find that the E3 ligase neural precursor cell expressed, developmentally down-regulated 4 (Nedd4) is enriched in synaptosomes and co-localizes and associates with AMPARs in neurons. Nedd4 expression leads to AMPAR ubiquitination, leading to reduced AMPAR surface expression and suppressed excitatory synaptic transmission. Conversely, knockdown of Nedd4 by specific siRNAs abolishes AMPAR ubiquitination. These data indicate that Nedd4 is the E3 ubiquitin ligase responsible for AMPAR ubiquitination, a modification that regulates multiple aspects of AMPAR molecular biology including trafficking, localization and stability.

| S-EPMC3110981 | biostudies-literature

Transferrin Receptor Controls AMPA Receptor Trafficking Efficiency and Synaptic Plasticity.

Project description:Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure, and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity.

| S-EPMC4754636 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data