Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor is densely distributed in the mammalian brain and is primarily involved in mediating fast excitatory synaptic transmission. Recent studies in both heterologous expression systems and cultured neurons have shown that the AMPA receptor can be phosphorylated on their subunits (GluR1, GluR2, and GluR4). All phosphorylation sites reside at serine, threonine, or tyrosine on the intracellular C-terminal domain. Several key protein kinases, such as protein kinase A, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and tyrosine kinases (Trks; receptor or nonreceptor family Trks) are involved in the site-specific regulation of the AMPA receptor phosphorylation. Other glutamate receptors (N-methyl-d-aspartate receptors and metabotropic glutamate receptors) also regulate AMPA receptors through a protein phosphorylation mechanism. Emerging evidence shows that as a rapid and short-term mechanism, the dynamic protein phosphorylation directly modulates the electrophysiological, morphological (externalization and internalization trafficking and clustering), and biochemical (synthesis and subunit composition) properties of the AMPA receptor, as well as protein-protein interactions between the AMPA receptor subunits and various intracellular interacting proteins. These modulations underlie the major molecular mechanisms that ultimately affect many forms of synaptic plasticity.
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PMID:Phosphorylation of AMPA receptors: mechanisms and synaptic plasticity. 1638 40

Kainate receptors (KARs) are widely expressed the basal ganglia. In this study, we used electron microscopic immunocytochemistry and whole-cell recording techniques to examine the localization and function of KARs in the rat globus pallidus (GP). Dendrites were the most common immunoreactive elements, while terminals forming symmetric or asymmetric synapses and unmyelinated axons comprised most of the presynaptic labeling. To determine whether synaptically released glutamate activates KARs, we recorded excitatory postsynaptic currents (EPSCs) in the GP following single-pulse stimulation of the internal capsule. 4-(8-Methyl-9H-1,3-dioxolo[4,5 h]{2,3}benzodiazepine-5-yl)-benzenamine hydrochloride (GYKI 52466, 100 microm), an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, reduced but did not completely block evoked EPSCs. The remaining EPSC component was mediated through activation of KARs because it was abolished by 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), an AMPA/KAR antagonist. The rise time (10-90%) and decay time constant (tau) for those EPSCs were longer than those of AMPA-mediated EPSCs recorded before GYKI 52466 application. KAR activation inhibited EPSCs. This inhibition was associated with a significant increase in paired-pulse facilitation ratio, suggesting a presynaptic action of KAR. KAR inhibition of EPSCs was blocked by the G-protein inhibitor, N-ethylmaleimide (NEM), or the protein kinase C (PKC) inhibitor calphostin C. Our results demonstrate that KAR activation has dual effects on glutamatergic transmission in the rat GP: (1) it mediates small-amplitude EPSCs; and (2) it reduces glutamatergic synaptic transmission through a presynaptic G-protein coupled, PKC-dependent, metabotropic mechanism. These findings provide evidence for the multifarious functions of KARs in regulating synaptic transmission, and open up the possibility for the development of pharmacotherapies to reduce the hyperactive subthalamofugal projection in Parkinson's disease.
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PMID:Localization and function of pre- and postsynaptic kainate receptors in the rat globus pallidus. 1642 Apr 45

Ionotropic glutamate receptors, N-methyl-d-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), are densely distributed in the mammalian brain and actively regulate a variety of cellular activities. Expression and function of these receptors are also under a tight regulation by many molecular mechanisms. Protein phosphorylation represents one of the important mechanisms for the posttranslational modulation of these receptors. Constitutive and regulatory phosphorylation occurs at distinct sites (serine, threonine, or tyrosine) on the intracellular C-terminal domain of almost all subunits capable of assembling a functional channel. Several key protein kinases, such as protein kinase A, protein kinase C, Ca(2+)/calmodulin-dependent protein kinases, and tyrosine kinases are involved in the site-specific catalyzation and regulation of NMDAR and AMPAR phosphorylation. Through the phosphorylation mechanism, these protein kinases as well as protein phosphatases control biochemical properties (biosynthesis, delivery, and subunit assembling), subcellular distribution, and interactions of these receptors with various synaptic proteins, which ultimately modify the efficacy and strength of excitatory synapses containing NMDARs and AMPARs and many forms of synaptic plasticity. Emerging evidence shows that psychostimulants (cocaine and amphetamine) are among effective agents that profoundly alter the phosphorylation status of both receptors in striatal neurons in vivo. Thus, psychostimulants may modulate NMDAR and AMPAR function through the phosphorylation mechanism to shape the excitatory synaptic plasticity related to additive properties of drugs of abuse.
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PMID:Phosphorylation of glutamate receptors: a potential mechanism for the regulation of receptor function and psychostimulant action. 1698 60

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity in the hippocampus, but the mechanisms involved are not fully understood. The neurotrophin couples synaptic activation to changes in gene expression underlying long term potentiation and short term plasticity. Here we show that BDNF acutely up-regulates GluR1, GluR2, and GluR3 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits in 7-day in vitro cultured hippocampal neurons. The increase in GluR1 and GluR2 protein levels in developing cultures was impaired by K252a, a tropomyosin-related [corrected] kinase (Trk) inhibitor, and by translation (emetine and anisomycin) and transcription (alpha-amanitine and actinomycin D) inhibitors [corrected] The increase in GluR1 and GluR2 protein levels in developing cultures was impaired by K252a, a Trk inhibitor, and by translation (emetine and anisomycin) and transcription (alpha-amanitine and actinomycin D) inhibitors. Accordingly, BDNF increased the mRNA levels for GluR1 and GluR2 subunits. Biotinylation studies showed that stimulation with BDNF for 30 min selectively increased the amount of GluR1 associated with the plasma membrane, and this effect was abrogated by emetine. Under the same conditions, BDNF induced GluR1 phosphorylation on Ser-831 through activation of protein kinase C and Ca(2+)-calmodulin-dependent protein kinase II. Chelation of endogenous extracellular BDNF with TrkB-IgG selectively decreased GluR1 protein levels in 14-day in vitro cultures of hippocampal neurons. Moreover, BDNF promoted synaptic delivery of homomeric GluR1 AMPA receptors in cultured organotypic slices, by a mechanism independent of NMDA receptor activation. Taken together, the results indicate that BDNF up-regulates the protein levels of AMPA receptor subunits in hippocampal neurons and induces the delivery of AMPA receptors to the synapse.
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PMID:Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons. 1733 42

Long term potentiation and long term depression of synaptic responses in the hippocampus are thought to be critical for certain forms of learning and memory, although until recently it has been difficult to demonstrate that long term potentiation or long term depression occurs during hippocampus-dependent learning. Induction of long term potentiation or long term depression in hippocampal slices in vitro modulates phosphorylation of the alpha-amino-3-hydrozy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor subunit GluR1 at distinct phosphorylation sites. In long term potentiation, GluR1 phosphorylation is increased at the Ca2+/calmodulin-dependent protein kinase and protein kinase C site serine 831, whereas in long term depression, phosphorylation of the protein kinase A site serine 845 is decreased. Indeed, phosphorylation of one or both of these sites is required for long term synaptic plasticity and for certain forms of learning and memory. Here we demonstrate that training in a hippocampus-dependent learning task, contextual fear conditioning is associated with increased phosphorylation of GluR1 at serine 831 in the hippocampal formation. This increased phosphorylation is specific to learning, has a similar time course to that in long term potentiation, and like memory and long term potentiation, is dependent on N-methyl-D-aspartate receptor activation during training. Furthermore, the learning-induced increase in serine 831 phosphorylation is present at synapses and is in heteromeric complexes with the glutamate receptor subunit GluR2. These data indicate that a biochemical correlate of long term potentiation occurs at synapses in receptor complexes in a final, downstream, postsynaptic effector of long term potentiation during learning in vivo, further strengthening the link between long term potentiation and memory.
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PMID:Learning-induced glutamate receptor phosphorylation resembles that induced by long term potentiation. 1747 59

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor regulation has been shown to be critically involved in synaptic plasticity underlying learning and memory. This regulation occurs through trafficking of the receptor and modulation of the receptor's channel properties, both of which depend on protein phosphorylation. Using homologous recombination (knock-in) techniques we targeted two phosphorylation sites on the AMPA-GluR1 receptor: the Ser831 site, phosphorylated by calcium calmodulin-dependent protein kinase II/protein kinase C, and the Ser845 site, phosphorylated by protein kinase A. Mice with mutations that prevented phosphorylation at one or both of these sites were tested on a single-outcome Pavlovian-instrumental transfer task often used to assess the acquisition of incentive motivation by cues for food reinforcement. Mice were separately trained to associate a Pavlovian cue with food and to perform an instrumental lever-press response to earn that same reward. During a transfer test, the cue was presented while the mice were lever-pressing under extinction conditions. Whereas wild-type control mice showed substantial enhancement of lever-pressing when the cue was presented (i.e. showed Pavlovian-instrumental transfer), mice with mutations at both of these phosphorylation sites showed no evidence of such transfer. By contrast, mice with either serine site mutated alone showed normal transfer. These results suggest critical roles for GluR1 phosphorylation pathways in a form of incentive learning that can play an important part in regulating normal motivated behavior as well as maladaptive behaviors such as addiction and eating disorders.
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PMID:A role for alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid GluR1 phosphorylation in the modulatory effects of appetitive reward cues on goal-directed behavior. 1859 67

Protein phosphorylation is an important mechanism for the post-translational modulation of ionotropic glutamate receptors. In this study, we investigated the regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR1 subunit phosphorylation by the stimulation of group I metabotropic glutamate receptors (mGluRs) in the rat dorsal striatum in vivo. Stimulation of group I mGluRs was found to increase GluR1 phosphorylation of Ser831 and Ser845 in phospholipase C (PLC)-coupled Ca(2+) cascades. Interactions of protein kinases activated by intracellular Ca(2+) release downstream to PLC modulate the phosphorylation state of GluR1 on Ser831 and Ser845: phosphorylation of GluR1 on Ser831 is up-regulated by the protein kinase C and calcium-calmodulin-dependent protein kinase (CaMK)/c-Jun N-terminal kinase (JNK) pathways, whereas phosphorylation of GluR1 on Ser845 is up-regulated by the protein kinase A (PKA), PKA/ERK1/2, and PKA/JNK pathways. The phosphorylation state of GluR1 on Ser831 and Ser845 and the activity of protein kinases are further regulated by protein phosphatases. These data suggest that GluR1 phosphorylation of Ser831 and Ser845 via stimulation of group I mGluRs is regulated by the interactions of PLC-coupled protein kinases and protein phosphatases in the dorsal striatum.
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PMID:Activation of group I metabotropic glutamate receptors increases serine phosphorylation of GluR1 alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the rat dorsal striatum. 1925 22

In the sympathetic nervous system, ATP is a co-transmitter and modulator of transmitter release, inhibiting noradrenaline release by acting on P2Y autoreceptors, but in peripheral tissues the subtypes involved have only scarcely been identified. We investigated the identity of the noradrenaline release-inhibiting P2Y subtypes in the epididymal portion of vas deferens and tail artery of the rat. The subtypes operating as autoreceptors, the signalling mechanism and cross-talk with alpha(2)-autoreceptors, was also investigated in the epididymal portion. In both tissues, the nucleotides 2-methylthioATP, 2-methylthioADP, ADP and ATP inhibited noradrenaline release up to 68%, with the following order of potency: 2-methylthioADP=2-methylthioATP>ADP=ATP in the epididymal portion and 2-methylthioADP=2-methylthioATP=ADP>ATP in the tail artery. The selective P2Y(1) antagonist 2'-deoxy-N(6)-methyladenosine 3',5'-bisphosphate (30microM) and the P2Y(12) antagonist 2,2-dimethyl-propionic acid 3-(2-chloro-6-methylaminopurin-9-yl)-2-(2,2-dimethyl-propionyloxymethyl)-propyl ester (30microM) increased noradrenaline release per se by 25+/-8% and 18+/-3%, respectively, in the epididymal portion but not in tail artery. Both antagonists attenuated the effect of nucleotides in the epididymal portion whereas in tail artery only the P2Y(1) antagonist was effective. The agonist of P2Y(1) and P2Y(12) receptors, 2-methylthioADP, caused an inhibition of noradrenaline release that was not prevented by inhibition of phospholipase C or protein kinase C but was abolished by pertussis toxin. 2-methylthioADP and the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine were less potent at inhibiting noradrenaline release under marked influence of alpha(2)-autoinhibition. In both tissues, nucleotides modulate noradrenaline release by activation of inhibitory P2Y(1) receptors but in the epididymal portion P2Y(12) receptors also participate. P2Y(1) and P2Y(12) receptors are coupled to G(i/o)-proteins and operate as autoreceptors in the vas deferens where they interact with alpha(2)-adrenoceptors on the modulation of noradrenaline release.
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PMID:The P2Y(1) and P2Y(12) receptors mediate autoinhibition of transmitter release in sympathetic innervated tissues. 1944 54

Protein phosphorylation is an important mechanism for the posttranslational modulation of ionotropic glutamate receptors and is subject to regulation by changing synaptic inputs. In this study, we investigated the regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR1 subunit phosphorylation by cocaine exposure in the rat dorsal striatum in vivo. We found that acute cocaine challenge followed by 6 days of repeated systemic injections of cocaine (20 mg/kg once daily) enhanced the sensitivity of the GluR1 subunit in its phosphorylation at serine 831 (Ser831) in the dorsal striatum. This enhancement of the sensitivity of Ser831 phosphorylation was reduced, at the receptor and ion channel level, by blocking (1) group I metabotropic glutamate receptors (mGluRs), (2) N-methyl-D-aspartate receptors, and (3) L-type voltage-operated Ca(2+) channels. Similar reduction of the enhancement was also induced, at the protein kinase level, by inhibiting (1) protein kinase C, (2) calcium/calmodulin-dependent protein kinases, and (3) c-Jun N-terminal kinases. In addition, inhibition of protein phosphatase 1/2A or calcineurin increased GluR1-Ser831 phosphorylation in the dorsal striatum of normal rats, whereas inhibition of these phosphatases did not further enhance the Ser831 phosphorylation in rats pretreated with 7 daily injections of cocaine. These data suggest that the phosphorylation of AMPA receptor GluR1 subunits at Ser831 is subject to upregulation by acute and repeated cocaine administration. Complex signaling integrations among glutamate receptors, Ca(2+) channels, protein kinases, and protein phosphatases participate in this upregulation.
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PMID:Alterations in AMPA receptor phosphorylation in the rat striatum following acute and repeated cocaine administration. 1955 63

The protein interacting with C kinase 1 (PICK1) protein was first identified as a novel binding partner for protein kinase C. PICK1 contains a membrane-binding BAR domain and a PDZ domain interacting with many synaptic proteins, including the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR2 and the dopamine transporter. PICK1 is strongly implicated in GluR2 trafficking and synaptic plasticity. In mammals, PICK1 has been characterized extensively in cell culture studies. To study PICK1 in an intact system, we characterized PICK1 expression immunohistochemically in the adult and larval Drosophila central nervous system. PICK1 was found in cell bodies in the subesophageal ganglion, the antennal lobe, the protocerebrum, and the neuroendocrine center pars intercerebralis. The cell types that express PICK1 were identified using GAL4 enhancer trap lines. The PICK1-expressing cells form a subpopulation of neurons. PICK1 immunoreactivity was neither detected in glutamatergic nor in dopaminergic neurons. Also, we observed PICK1 expression in only a few GABAergic neurons, located in the antennal lobe. In contrast, we detected robust PICK1 immunolabeling of peptidergic neurons in the neuroendocrine system, which express the transcription factor DIMM and the amidating enzyme peptidylglycine-alpha-hydroxylating monooxygenase (PHM). The PICK1-positive cells include neurosecretory cells that produce the insulin-like peptide dILP2. PICK1 expression in insulin-producing cells also occurs in mammals, as it was also observed in a rat insulinoma cell line derived from pancreatic beta-cells. At the subcellular level, PICK1 was found in the perinuclear zone but surprisingly not in synaptic domains. We conclude that PICK1 may serve an important role in the neuroendocrine system both in insects and vertebrates.
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PMID:PICK1 expression in the Drosophila central nervous system primarily occurs in the neuroendocrine system. 1975 95


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