Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5

Hou, Hailong; Sun, Lu; Siddoway, Benjamin; Petralia, Ronald S.; Yang, Hongtian; Gu, Hua; Nairn, Angus C.; Xia, Houhui

doi:10.1083/jcb.201303035

Cited by 59 publications

(34 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results agree with previous studies demonstrating that tPA has a homeostatic effect in the synapse under physiological and pathological conditions (Wu et al, 2012, 2013b; Yepes, 2015). Importantly, our data indicate that as shown by others (Hou et al, 2013) the baseline levels of PP1 phosphorylated at T35 are almost undetectable, and that tPA does not have an effect on I-1 phosphorylation at T35. Instead, our results indicate that tPA has a direct effect on PP1 phosphorylation at T320.…”

Section: Discussionsupporting

confidence: 81%

“…Recent studies have found that Cdk-5-induced phosphorylation of PP1 at T320 (pPP1) is a calcineurin-independent mechanism for PP1 inactivation that plays a central role in the development of synaptic plasticity (Hou et al, 2013). Thus, to investigate whether PP1 inactivation by its phosphorylation at T320 mediates tPA-induced CaMKIIα phosphorylation and recruitment to the PSD in neurons with low baseline levels of pCaMKIIα, we studied the expression of pPP1 (T320) in PSD extracts prepared from Wt cerebral cortical neurons treated with 5 nM of tPA or vehicle (control) in the presence or absence of the Cdk5 inhibitor Rosc.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the relevance of these observations, recent experimental evidence has uncovered calcineurin- and I-1-independent mechanisms for the regulation of neuronal PP1 activity. For example, cyclin-dependent kinase 5 (Cdk5)-induced PP1 phosphorylation at T320 inhibits PP1 by blocking access to its substrates (Goldberg et al, 1995); importantly, several studies indicate that this mechanism of PP1 regulation is pivotal for the control of the G2/M phase of the cell cycle (Kwon et al, 1997) and the development of synaptic plasticity (Hou et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tissue-type Plasminogen Activator (tPA) Modulates the Postsynaptic Response of Cerebral Cortical Neurons to the Presynaptic Release of Glutamate

Jeanneret

Merino

et al. 2016

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Tissue-type plasminogen activator (tPA) is a serine proteinase released by the presynaptic terminal of cerebral cortical neurons following membrane depolarization (Echeverry et al., 2010). Recent studies indicate that the release of tPA triggers the synaptic vesicle cycle and promotes the exocytosis (Wu et al., 2015) and endocytic retrieval (Yepes et al., 2016) of glutamate-containing synaptic vesicles. Here we used electron microscopy, proteomics, quantitative phosphoproteomics, biochemical analyses with extracts of the postsynaptic density (PSD), and an animal model of cerebral ischemia with mice overexpressing neuronal tPA to study whether the presynaptic release of tPA also has an effect on the postsynaptic terminal. We found that tPA has a bidirectional effect on the composition of the PSD of cerebral cortical neurons that is independent of the generation of plasmin and the presynaptic release of glutamate, but depends on the baseline level of neuronal activity and the extracellular concentrations of calcium (Ca2+). Accordingly, in neurons that are either inactive or incubated with low Ca2+ concentrations tPA induces phosphorylation and accumulation in the PSD of the Ca2+/calmodulin-dependent protein kinase IIα (pCaMKIIα), followed by pCaMKIIα-mediated phosphorylation and synaptic recruitment of GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast, in neurons with previously increased baseline levels of pCaMKIIα in the PSD due to neuronal depolarization in vivo or incubation with high concentrations of either Ca2+ or glutamate in vitro, tPA induces pCaMKIIα and pGluR1 dephosphorylation and their subsequent removal from the PSD. We found that these effects of tPA are mediated by synaptic N-methyl-D-aspartate (NMDA) receptors and cyclin-dependent kinase 5 (Cdk5)-induced phosphorylation of the protein phosphatase 1 (PP1) at T320. Our data indicate that by regulating the pCaMKIIα/PP1 balance in the PSD tPA acts as a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tissue-type Plasminogen Activator (tPA) Modulates the Postsynaptic Response of Cerebral Cortical Neurons to the Presynaptic Release of Glutamate

Jeanneret

Merino

et al. 2016

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…To further confirm these results, we used an alternative method of stimulation. It is known that synaptic NMDA receptors can be activated by treating neurons with a combination of a potassium channel antagonist and a GABA A receptor antagonist [ 27 , 28 , 29 ]. Thus, we stimulated hippocampal neurons with PTX and 4-aminopyridine (4-AP), a potassium channel antagonist.…”

Section: Resultsmentioning

confidence: 99%

MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism

Bernard

Zhang

2015

PLoS ONE

View full text Add to dashboard Cite

The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs), are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer’s disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippocampal neurons. Further, we show that this activation is dependent on protein kinase A (PKA), through the phosphorylation of Ser431 of Par4/LKB1, the major upstream kinase of MARK/Par1. Together, our data reveal a novel mechanism by which MARK/Par1 is activated at the neuronal synapse.

show abstract

“…It is reported that stimulation of synaptic NMdARs leads to a decrease in Cdk5 activity. 35 NO production, and in turn, Cdk5 SNO activate Cdk5. MK-801 blocks both synaptic NMdARs and NMdAR-PSd-95-nNOS-NO pathway.…”

Section: Discussionmentioning

confidence: 99%

Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats

Zhou

Tang

Zhang

et al. 2015

Stroke

View full text Add to dashboard Cite

Background and Purpose— Previous studies reported that Tat-NR2B9c, a peptide disrupting the N -methyl- d -aspartate receptor–postsynaptic density protein-95 interaction, reduced ischemic damage in the acute phase after stroke. However, its effect in the subacute phase is unknown. The aim of this study is to determine whether disrupting the N -methyl- d -aspartate receptor–postsynaptic density protein-95 interaction in the subacute phase promotes recovery after stroke. Methods— Studies were performed on Sprague-Dawley rats or nNOS −/− mice, and experimental ischemic stroke was induced by middle cerebral artery occlusion. Animals were treated with drugs starting at day 4 after ischemia. Sensorimotor functions and spatial learning and memory ability were assessed after drug treatment. Then, rats were euthanized for morphological observation and biochemical tests. Results— Disrupting the N -methyl- d -aspartate receptor–postsynaptic density protein-95 interaction with Tat-HA-NR2B9c significantly ameliorated the ischemia-induced impairments of spatial memory and sensorimotor functions in rats during subacute stage but did not improve stroke outcome in nNOS −/− mice. Consistent with the functional recovery, Tat-HA-NR2B9c substantially increased neurogenesis in the dentate gyrus and dendritic spine density of mature neurons in the motor cortex of rats, meanwhile, reversed the ischemia-induced formation of S -nitrosylation-cyclin-dependent kinase 5 and increased cyclin-dependent kinase 5 activity in ipsilateral hippocampus. However, directly blocking N -methyl- d -aspartate receptors with MK-801 or Ro 25-6981 did not show the beneficial effects above. Conclusions— Dissociating N -methyl- d -aspartate receptor–postsynaptic density protein-95 coupling by Tat-HA-NR2B9c in the subacute phase after stroke promotes functional recovery, probably because of that it increases neurogenesis and dendritic spine density of mature neurons via regulating cyclin-dependent kinase 5 in the ischemic brain.

show abstract

Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5

Abstract: Synaptic stimulation promotes proteasome-dependent degradation of p35, inactivation of Cdk5, and decreased phosphorylation of PP1, allowing PP1 to act in the induction of long-term depression.

Cited by 59 publications

References 61 publications

Tissue-type Plasminogen Activator (tPA) Modulates the Postsynaptic Response of Cerebral Cortical Neurons to the Presynaptic Release of Glutamate

Tissue-type Plasminogen Activator (tPA) Modulates the Postsynaptic Response of Cerebral Cortical Neurons to the Presynaptic Release of Glutamate

MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism

Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats

Contact Info

Product

Resources

About