Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.17 (CaMKII)
4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the mechanisms underlying synaptic plasticity at the layer IV to II/III pathway in barrel cortex of mice aged 6-13 weeks. This pathway is one of the likely candidates for expression of experience-dependent plasticity in the barrel cortex and may serve as a model for other IV to II/III synapses in the neocortex. We found that postsynaptic autocamtide-2-inhibitory peptide is sufficient to block long-term potentiation (LTP) (IC50 of 500 nm), implicating postsynaptic calcium/calmodulin-dependent kinase II in LTP induction. AMPA receptor subunit 1 (GluR1) knock-out mice also showed LTP in this pathway, but potentiation was predominantly presynaptic in origin as determined by paired-pulse analysis, coefficient of variation analysis, and quantal analysis, whereas wild types showed a mixed presynaptic and postsynaptic locus. Quantal analysis at this synapse was validated by measuring uniquantal events in the presence of strontium. The predominantly presynaptic LTP in the GluR1 knock-outs was blocked by postsynaptic antagonism of nitric oxide synthase (NOS), either with intracellular N-omega-nitro-L-arginine methyl ester or N-nitro-L-arginine, providing the first evidence for a retrograde transmitter role for NO at this synapse. Antagonism of NOS in wild types significantly reduced but did not eliminate LTP (group average reduction of 50%). The residual LTP formed a variable proportion of the total LTP in each cell and was found to be postsynaptic in origin. We found no evidence for silent synapses in this pathway at this age. Finally, application of NO via a donor induced potentiation in layer II/III cells and caused an increase in frequency but not amplitude of miniature EPSPs, again implicating NO in presynaptic plasticity.
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PMID:The role of nitric oxide and GluR1 in presynaptic and postsynaptic components of neocortical potentiation. 1683 87

Postsynaptic nitric oxide (NO) production affects synaptic plasticity and neuronal cell death. Ca2+ fluxes through the NMDA receptor (NMDAR) stimulate the production of NO by neuronal nitric oxide synthase (nNOS). However, the mechanisms by which nNOS activity is regulated are poorly understood. We evaluated the effect of neuronal stimulation with glutamate on the phosphorylation of nNOS. We show that, in cortical neurons, a low glutamate concentration (30 microM) induces rapid and transient NMDAR-dependent phosphorylation of S1412 by Akt, followed by sustained phosphorylation of S847 by CaMKII (calcium-calmodulin-dependent kinase II). We demonstrate that phosphorylation of S1412 by Akt is necessary for activation of nNOS by the NMDAR. nNOS mutagenesis confirms that these phosphorylations respectively activate and inhibit nNOS and, thus, transiently activate NO production. A constitutively active (S1412D), but not a constitutively repressed (S847D) nNOS mutant elevated surface glutamate receptor 2 levels, demonstrating that these phosphorylations can control AMPA receptor trafficking via NO. Notably, an excitotoxic stimulus (150 microM glutamate) induced S1412, but not S847 phosphorylation, leading to deregulated nNOS activation. S1412D did not kill neurons; however, it enhanced the excitotoxicity of a concomitant glutamate stimulus. We propose a swinging domain model for the regulation of nNOS: S1412 phosphorylation facilitates electron flow within the reductase module of nNOS, increasing nNOS sensitivity to Ca2+-calmodulin. These findings suggest a critical role for a kinetically complex and novel series of regulatory nNOS phosphorylations induced by the NMDA receptor for the in vivo control of nNOS.
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PMID:Biphasic coupling of neuronal nitric oxide synthase phosphorylation to the NMDA receptor regulates AMPA receptor trafficking and neuronal cell death. 1739 61

The alpha-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) is an ionotropic glutamate receptor that governs most of excitatory synaptic transmission in neurons. In vitro biochemical assay has shown that calpain, a Ca2+-activated protease, can cleave AMPAR GluR1 subunits. Our physiological study found that calpain, which was activated by prolonged stimulation of the N-methyl-D-aspartate receptor (100 microM, 10 min), caused a substantial suppression of AMPAR currents in cortical neurons. Since the phosphorylation sites of GluR1 by several protein kinases are located in close proximity to the calpain cleavage sites, we investigated the effect of phosphorylation on the susceptibility of GluR1 to calpain cleavage. Interestingly, we found that the calpain regulation of AMPAR currents was diminished by inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) but was augmented by inhibition of protein phosphatase 1/2A (PP1/2A). In agreement with this, in vitro assay showed that the calpain-induced proteolytic cleavage of GluR1 C-terminal fusion protein was strongly potentiated by adding the purified active CaMKII, and GluR1 phosphorylated at Ser831 by CaMKII is much more sensitive to calpain cleavage. Taken together, our data suggest that calpain activation suppresses AMPA receptor currents via proteolytic cleavage of GluR1 subunits, and the susceptibility of AMPARs to calpain cleavage is determined by the phosphorylation state of GluR1 subunits, which is mediated by CaMKII-PP1/2A activity.
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PMID:The phosphorylation state of GluR1 subunits determines the susceptibility of AMPA receptors to calpain cleavage. 1742 97

Evidence is accumulating for a role for amyloid peptides in impaired synaptic plasticity and cognition, while the underlying mechanisms remain unclear. We here analyzed the effects of amyloid peptides on NMDA-receptor function in vitro and in vivo. A synthetic amyloid peptide preparation containing monomeric and oligomeric A beta (1-42) peptides was used and demonstrated to bind to synapses expressing NMDA-receptors in cultured hippocampal and cortical neurons. Pre-incubation of primary neuronal cultures with A beta peptides significantly inhibited NMDA-receptor function, albeit not by a direct pharmacological inhibition of NMDA-receptors, since acute application of A beta peptides did not change NMDA-receptor currents in autaptic hippocampal cultures nor in xenopus oocytes expressing recombinant NMDA-receptors. Pre-incubation of primary neuronal cultures with A beta peptides however decreased NR2B-immunoreactive synaptic spines and surface expression of NR2B containing NMDA-receptors. Furthermore, we extended these findings for the first time in vivo, demonstrating decreased concentrations of NMDA-receptor subunit NR2B and PSD-95 as well as activated alpha-CaMKII in postsynaptic density preparations of APP[V717I] transgenic mice. This was associated with impaired NMDA-dependent LTP and decreased NMDA- and AMPA-receptor currents in hippocampal CA1 region in APP[V717I] transgenic mice. In addition, induction of c-Fos following cued and contextual fear conditioning was significantly impaired in the basolateral amygdala and hippocampus of APP[V717I] transgenic mice. Our data demonstrate defects in NMDA-receptor function and learning dependent signaling cascades in vivo in APP[V717I] transgenic mice and point to decreased surface expression of NMDA-receptors as a mechanism involved in early synaptic defects in APP[V717I] transgenic mice in vivo.
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PMID:Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice. 1767 36

Activity-dependent rapid structural and functional modifications of central excitatory synapses contribute to synapse maturation, experience-dependent plasticity, and learning and memory and are associated with neurodevelopmental and psychiatric disorders. However, the signal transduction mechanisms that link glutamate receptor activation to intracellular effectors that accomplish structural and functional plasticity are not well understood. Here we report that NMDA receptor activation in pyramidal neurons causes CaMKII-dependent phosphorylation of the guanine-nucleotide exchange factor (GEF) kalirin-7 at residue threonine 95, regulating its GEF activity, leading to activation of small GTPase Rac1 and rapid enlargement of existing spines. Kalirin-7 also interacts with AMPA receptors and controls their synaptic expression. By demonstrating that kalirin expression and spine localization are required for activity-dependent spine enlargement and enhancement of AMPAR-mediated synaptic transmission, our study identifies a signaling pathway that controls structural and functional spine plasticity.
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PMID:Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. 1803 82

Phosphorylation-dependent changes in AMPA receptor function have a crucial role in activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Although three previously identified phosphorylation sites in AMPA receptor glutamate receptor 1 (GluR1) subunits (S818, S831, and S845) appear to have important roles in LTP and LTD, little is known about the role of other putative phosphorylation sites in GluR1. Here, we describe the characterization of a recently identified phosphorylation site in GluR1 at threonine 840. The results of in vivo and in vitro phosphorylation assays suggest that T840 is not a substrate for protein kinases known to phosphorylate GluR1 at previously identified phosphorylation sites, such as protein kinase A, protein kinase C, and calcium/calmodulin-dependent kinase II. Instead, in vitro phosphorylation assays suggest that T840 is a substrate for p70S6 kinase. Although LTP-inducing patterns of synaptic stimulation had no effect on GluR1 phosphorylation at T840 in the hippocampal CA1 region, bath application of NMDA induced a strong, protein phosphatase 1- and/or 2A-mediated decrease in T840 phosphorylation. Moreover, GluR1 phosphorylation at T840 was transiently decreased by a chemical LTD induction protocol that induced a short-term depression of synaptic strength and persistently decreased by a chemical LTD induction protocol that induced a lasting depression of synaptic transmission. Together, our results show that GluR1 phosphorylation at T840 is regulated by NMDA receptor activation and suggest that decreases in GluR1 phosphorylation at T840 may have a role in LTD.
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PMID:NMDA receptor activation dephosphorylates AMPA receptor glutamate receptor 1 subunits at threonine 840. 1804 15

Depression is associated with abnormal neuronal plasticity. AMPA receptors mediate transmission and plasticity at excitatory synapses in a manner which is positively regulated by phosphorylation at Ser831-GluR1, a CaMKII/PKC site, and Ser845-GluR1, a PKA site. Treatment with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor fluoxetine increases P-Ser845-GluR1 but not P-Ser831-GluR1. Here, it was found that treatment with another antidepressant, tianeptine, increased P-Ser831-GluR1 in the frontal cortex and the CA3 region of hippocampus and P-Ser845-GluR1 in the CA3 region of hippocampus. A receptorome profile detected no affinity for tianeptine at any monaminergic receptors or transporters, confirming an atypical profile for this compound. Behavioural analyses showed that mice bearing point mutations at both Ser831- and Ser845-GluR1, treated with saline, exhibited increased latency to enter the centre of an open field and increased immobility in the tail-suspension test compared to their wild-type counterparts. Chronic tianeptine treatment increased open-field locomotion and reduced immobility in wild-type mice but not in phosphomutant GluR1 mice. P-Ser133-CREB was reduced in the CA3 region of hippocampus in phosphomutant mice, and tianeptine decreased P-Ser133-CREB in this region in wild-type, but not in phosphomutant, mice. Tianeptine increased P-Ser133-CREB in the CA1 region in wild-type mice but not in phosphomutant GluR1 mice. There were higher basal P-Ser133-CREB and c-fos levels in frontal and cingulate cortex in phosphomutant GluR1 mice; these changes in level were counteracted by tianeptine in a GluR1-independent manner. Using phosphorylation assays and phosphomutant GluR1 mice, this study provides evidence that AMPA receptor phosphorylation mediates certain explorative and antidepressant-like actions under basal conditions and following tianeptine treatment.
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PMID:Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. 1808 78

The trafficking of postsynaptic AMPA receptors (AMPARs) is a powerful mechanism for regulating the strength of excitatory synapses. It has become clear that the surface levels of inhibitory GABA(A) receptors (GABA(A)Rs) are also subject to regulation and that GABA(A)R trafficking may contribute to inhibitory plasticity, although the underlying mechanisms are not fully understood. Here, we report that NMDA receptor activation, which has been shown to drive excitatory long-term depression through AMPAR endocytosis, simultaneously increases expression of GABA(A)Rs at the dendritic surface of hippocampal neurons. This NMDA stimulus increases miniature IPSC amplitudes and requires the activity of Ca2+ calmodulin-dependent kinase II and the trafficking proteins N-ethylmaleimide-sensitive factor, GABA receptor-associated protein (GABARAP), and glutamate receptor interacting protein (GRIP). These data demonstrate for the first time that endogenous GABARAP and GRIP contribute to the regulated trafficking of GABA(A)Rs. In addition, they reveal that the bidirectional trafficking of AMPA and GABA(A) receptors can be driven by a single glutamatergic stimulus, providing a potent postsynaptic mechanism for modulating neuronal excitability.
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PMID:NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABA(A) receptors. 1816 Jun 40

Neurabin is a scaffolding protein that interacts with actin and protein phosphatase-1. Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation. However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions. Using neurabin knockout (KO) mice, here we studied the function of neurabin in hippocampal synaptic transmission, plasticity and behavioral memory. We demonstrated that neurabin KO mice showed a deficit in contextual fear memory but not auditory fear memory. Whole-cell patch clamp recordings in the hippocampal CA1 neurons showed that long-term potentiation (LTP) was significantly reduced, whereas long-term depression (LTD) was unaltered in neurabin KO mice. Moreover, increased AMPA receptor but not NMDA receptor-mediated synaptic transmission was found in neurabin KO mice, and is accompanied by decreased phosphorylation of GluR1 at the PKA site (Ser845) but no change at the CaMKII/PKC site (Ser831). Pre-conditioning with LTD induction rescued the following LTP in neurabin KO mice, suggesting the loss of LTP may be due to the saturated synaptic transmission. Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.
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PMID:Neurabin contributes to hippocampal long-term potentiation and contextual fear memory. 1818 88

The regulated trafficking of neurotransmitter receptors at synapses is critical for synaptic function and plasticity. However, the molecular machinery that controls active transport of receptors into synapses is largely unknown. We found that, in rat hippocampus, the insertion of AMPA receptors (AMPARs) into spines during synaptic plasticity requires a specific motor protein, which we identified as myosin Va. We found that myosin Va associates with AMPARs through its cargo binding domain. This interaction was enhanced by active, GTP-bound Rab11, which is also transported by the motor protein. Myosin Va mediated the CaMKII-triggered translocation of GluR1 receptors from the dendritic shaft into spines, but it was not required for constitutive GluR2 trafficking. Accordingly, myosin Va was specifically required for long-term potentiation, but not for basal synaptic transmission. In summary, we identified the specific motor protein and organelle acceptor that catalyze the directional transport of AMPARs into spines during activity-dependent synaptic plasticity.
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PMID:Motor protein-dependent transport of AMPA receptors into spines during long-term potentiation. 1831 Nov 35


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