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:10.1085/jgp.1426oia46

Cited by 21 publications

(46 citation statements)

References 54 publications

(75 reference statements)

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“…Besides, Cdk5 is also involved in synaptogenesis downstream signaling [96]. In addition, massive studies have revealed Cdk5 participates in synaptic plasticity and memory formation via as a significant regulator of protein phosphatase PP1 [97] and PKA signaling as well as brain-derived neurotrophic factor (BDNF) receptor TrkB [98].…”

Section: Cdk5 Modulates Synaptic Plasticitymentioning

confidence: 99%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

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Section: Cdk5 Modulates Synaptic Plasticitymentioning

confidence: 99%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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“…However, several additional PP1 regulatory mechanisms have recently received attention in NMDAR signaling, including PP1 binding to inhibitor-2 (I-2), possibly in a ternary complex with neurabin-1, and PP1 inhibitory phosphorylation on Thr-320. In particular, recent work identified cyclin-dependent kinase 5 (CDK5) as the kinase for PP1 Thr-320 and demonstrated that when CDK5 is inhibited by synaptic NMDAR activation via proteasomal degradation of its p35 subunit, PP1 auto-dephosphorylates to become active (79). This study also uncovered a requirement for association of PP1 with I-2, which was increased by I-2 Thr-72 dephosphorylation, to promote PP1 signaling during NMDAR LTD; this mechanism stands in contrast with reversal of PP1 association with I-1 through Thr-35 dephosphorylation.…”

Section: Regulation Of Postsynaptic Pp1 Signalingmentioning

confidence: 99%

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

Woolfrey

Dell’Acqua

2015

Journal of Biological Chemistry

113

105

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A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity. Control of Synaptic Strength through Balanced Phosphorylation/DephosphorylationA defining aspect of the mammalian brain is its profound capacity for experience-dependent plasticity that modifies the strength of specific synaptic connections between neurons. Two well studied opposing forms of synaptic plasticity at excitatory synapses are long-term potentiation (LTP) 2 and longterm depression (LTD), which strengthen and weaken synapses, respectively. LTP and LTD have been most heavily studied in a brain region called the hippocampus where they support spatial and declarative learning and memory. LTP and LTD are induced by Ca 2ϩ influx through postsynaptic NMDAtype ionotropic glutamate receptors (NMDARs) and are expressed by long-lasting increases or decreases, respectively, in the function of AMPA-type ionotropic glutamate receptors (AMPARs) that mediate the bulk of excitatory synaptic transmission (1, 2). NMDARs are heterotetrameric assemblies most commonly containing two GluN1 and two GluN2A-2D subunits and are permeable to Na ϩ , K ϩ , and Ca 2ϩ . At hippocampal synapses, NMDARs are assembled from GluN1, GluN2A, and GluN2B subunits. AMPARs are heterotetrameric assemblies of GluA1-GluA4 subunits, with most being permeable only to Na ϩ and K ϩ due to inclusion of GluA2 subunits that prevent Ca 2ϩ influx (3). However, hippocampal neurons can also express small numbers of Ca 2ϩ -permeable AMPARs lacking GluA2 subunits (i.e. GluA1 homomers) that primarily reside in extrasynaptic and intracellular locations but can be recruited to synapses during plasticity and following neuronal injuries (4). Intriguingly, there is much commonality in the molecular mechanisms underlying the ostensibly antagonistic processes of LTP and LTD; both require correlated pre-and postsynaptic activity leading to NMDAR Ca 2ϩ influx and are mediated by overlapping sets of enzymes. However, it is the ability of the synapse to detect subtle differences in Ca 2ϩ and other second messengers and efficiently transduce these signals to discrete downstream signaling pathways that permits diametrically opposed outcomes to arise from grossly similar synaptic stimuli.Ultimately, excitatory synaptic plasticity must add, remove, or modify AMPARs to alter synaptic strength. Although AMPAR regulation during plas...

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“…) and the over‐stimulation of ion channels, which together promote the aggregation and formation of neurofibrillary tangles (Hou et al . ). Additionally, it has been previously shown that CDK5 silencing serves as a therapeutic strategy for AD (Lopez‐Tobon et al .…”

Section: Discussionmentioning

confidence: 97%

p120‐catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease

Uribe-Arias

Posada‐Duque

González-Billault

et al. 2016

Journal of Neurochemistry

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Cyclin-dependent kinase 5 (CDK5) plays important roles in synaptic function. Its unregulated over-activation has been, however, associated with neurodegeneration in Alzheimer’s disease. Our previous studies revealed that CDK5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTgAD mouse model. However, how CDK5 targeting affects synaptic adhesion proteins, such as those involved in the cadherin/catenin system, during learning and memory processes is not completely understood. In the present study, we detected reduced expression of p120 catenin (p120 ctn), N-cadherin, and β-catenin in the brain of human Alzheimer’s disease patients, in addition to a reduced PSD95 and GluN2B protein levels in a 3xTgAD mouse model. Such decrease in synaptic proteins was recovered by CDK5 silencing in mice leading to a better learning and memory performance. Additionally, CDK5 inhibition or knockout increased p120 ctn levels. Moreover in a glutamate-induced excitotoxicity model CDK5 silencing-induced neuroprotection depended on p120 ctn. Together, those findings suggest that p120 ctn plays an important role in the neuronal dysfunction of AD models and contributes to CDK5 silencing-induced neuroprotection and improvement of memory function.

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

Cited by 21 publications

References 54 publications

The Role of Cdk5 in Alzheimer’s Disease

The Role of Cdk5 in Alzheimer’s Disease

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

p120‐catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease

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