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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin is one of the first regulatory molecules present at sites of CNS trauma or injury. Exposure of neuronal and glial cells to thrombin produces potent morphological as well as cytoprotective and cytotoxic effects, but little is known about how this important modulator affects neurotransmitter signaling. In astrocyte cultures that have been morphologically differentiated by exposure to transforming growth factor-alpha, addition of thrombin induced a retraction of astrocytic processes and suppressed the stimulation of phosphoinositide hydrolysis by the selective metabotropic glutamate receptor (mGluR) agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid. In addition to the suppression of phosphoinositide hydrolysis, thrombin treatment produced a corresponding reduction in level of mGluR5 mRNA as demonstrated with ribonuclease protection assay and reduced content of mGluR5 receptor protein as seen with western blotting. In contrast, thrombin exposure up-regulated astrocyte beta-actin mRNA levels. A synthetic hexapeptide with a sequence corresponding to the amino-terminus of the thrombin receptor's tethered ligand also mimicked the ability of thrombin to suppress mGluR5 levels and to increase beta-actin mRNA content, suggesting that these effects of thrombin are mediated by proteolytically activated cell surface thrombin receptors. Thrombin's suppressive effect on mGluR5 was resistant to pretreatment with pertussis toxin or various protein kinase and protein phosphatase inhibitors. However, the serine/threonine protein kinase inhibitor H-7 did prevent thrombin-induced reversal of astrocyte stellation and induction of beta-actin mRNA levels, indicating that these effects of thrombin involve a signaling pathway distinct from the one that mediates the suppressive effects of thrombin on mGluR5.
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PMID:Exposure of astrocytes to thrombin reduces levels of the metabotropic glutamate receptor mGluR5. 885 25

Ammonia is a main factor in the pathogenesis of hepatic encephalopathy. We found that acute ammonia toxicity is mediated by activation of NMDA receptors. Chronic moderate hyperammonemia prevents acute ammonia toxicity in rats. Chronic exposure of cultured neurons to 1 mM ammonia leads to impaired response of the NMDA receptor to activation by its agonists (due to decreased protein kinase C-mediated phosphorylation) and prevents glutamate (Glu) neurotoxicity. Compounds that prevent ammonia toxicity in mice (e.g. carnitine) also prevent Glu toxicity in cultured neurons. These compounds did not prevent activation of NMDA receptor or the rise of Ca2+. They interfered with subsequent steps in the toxic process. The protective effect of carnitine is mediated by activation of metabotropic Glu receptors. Agonists of mGluRs, especially of mGluR5, prevent Glu toxicity. Agonists of muscarinic receptors also prevent Glu toxicity and there seems to be an interplay between muscarinic and metabotropic Glu receptors in the protective effect. We have tried to identify intracellular events involved in the process of neuronal death. It is known that the rise of Ca2+ is an essential step. Glu leads to depletion of ATP; some compounds (e.g. carnitine) prevent Glu-induced neuronal death without preventing ATP depletion: additional events are required for neuronal death. Glu induces activation of Na+/K+-ATPase, which could be involved in the toxic process. Inhibitors of protein kinase C, calcineurin or nitric oxide synthase prevent Glu toxicity. Our results indicate that Glu toxicity can be prevented at different steps or by activating receptors coupled to the transduction pathways interfering with the toxic process. Agents acting on these steps could prevent excitotoxicity in vivo in animals.
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PMID:Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. 974 28

The metabotropic glutamate receptor, mGluR5, has a critical role in induction of NMDA-receptor-dependent forms of synaptic plasticity and excitotoxicity. This is likely mediated by a reciprocal positive-feedback interaction between these two glutamate receptor subtypes in which activation of mGluR5 potentiates NMDA receptor currents and NMDA receptor activation potentiates mGluR5-mediated responses. We have investigated the mechanism by which NMDA receptor activation modulates mGluR5 function and find evidence that this response is mediated by activation of a protein phosphatase and a resultant dephosphorylation of protein kinase C phosphorylation sites on mGluR5. This form of neuromodulation may be important in a number of normal and pathological processes that involve activation of the NMDA receptor.
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PMID:Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. 1019 15

Glutamate regulates neuronal function by acting on ionotropic receptors such as the N-methyl-D-aspartate (NMDA) receptor and metabotropic receptors (mGluRs). We have previously shown that low concentrations of NMDA are able to significantly potentiate mGluR5 responses via activation of a protein phosphatase and reversal of phosphorylation-induced desensitization. While low concentrations of NMDA are able to potentiate mGluR5 responses, higher concentrations of NMDA are actually inhibitory. In this report, we show that NMDA receptors and mGluR5 are highly colocalized in cortical regions. We also show that in voltage-clamp recordings obtained from Xenopus oocytes expressing mGluR5 and NMDA receptors, high concentrations of NMDA (50-100 microM) that elicited large currents (>400 nA) caused an inhibition of mGluR5 currents. Additionally, agonist-induced phosphoinositide hydrolysis presumably mediated by activation of mGluR5, is inhibited by NMDA (30 microM and above). Additional data presented in this report suggest that the inhibitory effect of NMDA is caused by phosphorylation of mGluR5 at protein kinase C (PKC) sites since NMDA induces phosphorylation of the receptor as measured in a back phosphorylation assay.
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PMID:NMDA-induced phosphorylation and regulation of mGluR5. 1211 83

Protein phosphorylation, controlled by the coordinated actions of phosphatases and kinases, is an important regulatory mechanism in synaptic transmission and other neurophysiological processes. Ionotropic glutamate receptors are known targets of phosphorylation on serine, threonine and tyrosine residues, with functional consequences for cell excitability, plasticity and toxicity. While phosphorylation of metabotropic glutamate receptors (mGluRs) also impacts critical cellular processes, there has been no evidence for direct tyrosine phosphorylation of mGluRs. In the present study, anti-phosphotyrosine and specific mGluR antibodies were used to detect tyrosine-phosphorylated mGluRs in rat brain. In particular, we found that mGluR5 is an abundant phosphotyrosine protein in vivo as well as in primary striatal neurons and tissue slices in vitro. The protein phosphatase inhibitor pervanadate robustly increased the amount of tyrosine-phosphorylated mGluR5, suggesting the receptor is subject to an endogenous, active cycle of phosphorylation and dephosphorylation. Furthermore, NMDA treatment also increased the amount of tyrosine-phosphorylated mGluR5, suggesting these endogenous phosphorylation regulatory mechanisms can be used to mediate crosstalk between synaptic glutamate receptors. While mGluR5-stimulated phosphoinositide hydrolysis appears to be unaltered by pervanadate treatment, tyrosine phosphorylation of mGluR5 may be important in trafficking, anchoring, or signaling of the receptor through G protein-independent pathways.
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PMID:Tyrosine phosphorylation of the metabotropic glutamate receptor mGluR5 in striatal neurons. 1221 70

The ability of activation of group I metabotropic glutamate receptor (mGluR) to induce depotentiation was investigated at Schaffer collateral-CA1 synapses of rat hippocampal slices. Brief bath application (5 min) of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) (10 microm) induced a long-term depression of synaptic transmission or depotentiation (DEP) of previously established long-term potentiation (LTP), which was independent of NMDA or A(1) adenosine receptor activation. This DHPG-DEP was observed when DHPG was delivered 3 min after LTP induction. However, when DHPG was applied at 10 or 30 min after LTP induction, significantly less depotentiation was found. DHPG-DEP (1) is reversible and has the ability to unsaturate LTP, (2) is synapse specific, (3) does not require concurrent synaptic stimulation, (4) is mechanistically distinct from NMDA receptor-dependent depotentiation, (5) requires mGluR5 activation, (6) requires rapamycin-sensitive mRNA translation signaling, (7) does not require phospholipase C or protein phosphatase activation, and (8) is not associated with a change in paired-pulse (PP) facilitation. In addition, the ability of DHPG to reverse LTP was mimicked by a long train of low-frequency (1 Hz/15 min) PP stimulation. Moreover, the expression of DHPG-DEP is associated with a reduction in the increase of the surface expression of AMPA receptors seen with LTP. These results suggest that the activation of mGluR5 and in turn the triggering of a protein synthesis-dependent internalization of synaptic AMPA receptors may contribute to the DHPG-DEP in the CA1 region of the hippocampus.
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PMID:The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine induces a novel form of depotentiation in the CA1 region of the hippocampus. 1238 90

The electrosensory lobes (ELLs) of mormyrid and gymnotid fish are useful sites for studying plasticity and descending control of sensory processing. This study used immunocytochemistry to examine the functional circuitry of the mormyrid ELL. We used antibodies against the following proteins and amino acids: the neurotransmitters glutamate and gamma-aminobutyric acid (GABA); the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD); GABA transporter 1; the anchoring protein for GABA and glycine receptors, gephyrin; the calcium binding proteins calbindin and calretinin; the NR1 subunit of the N-methyl-D-aspartate glutamate receptor; the metabotropic glutamate receptors mGluR1alpha, mGluR2/3, and mGluR5; and the intracellular signaling molecules calcineurin, calcium calmodulin kinase IIalpha (CAMKIIalpha) and the receptor for inositol triphosphate (IP3R1alpha). Selective staining allowed for identification of new cell types including a deep granular layer cell that relays sensory information from primary afferent fibers to higher order cells of ELLS. Selective staining also allowed for estimates of relative numbers of different cell types. Dendritic staining of Purkinje-like medium ganglion cells with antibodies against metabotropic glutamate receptors and calcineurin suggests hypotheses concerning mechanisms of the previously demonstrated synaptic plasticity in these cells. Finally, several cell types including the above-mentioned granular cells, thick-smooth dendrite cells, and large multipolar cells of the intermediate layer were present in the two zones of ELL that receive input from mormyromast electroreceptors but were absent in the zone of ELL that receives input from ampullary electroreceptors, indicating markedly different processing for these two types of input. J. Comp. Neurol. 483:124-142, 2005. (c) 2005 Wiley-Liss, Inc.
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PMID:Immunocytochemical identification of cell types in the mormyrid electrosensory lobe. 1567 92

Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.
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PMID:NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin. 1600 30

Casein kinase 1 (CK1) is a highly conserved serine/threonine kinase, present in virtually all cell types, in which it phosphorylates a wide variety of substrates. So far, no role has been found for this ubiquitous protein kinase in the physiology of nerve cells. In the present study, we show that CK1 regulates fast synaptic transmission mediated by glutamate, the major excitatory neurotransmitter in the brain. Through the use of CK1 inhibitors, we present evidence that activation of CK1 decreases NMDA receptor activity in the striatum via a mechanism that involves activation by this kinase of protein phosphatase 1 and/or 2A and resultant increased dephosphorylation of NMDA receptors. Indeed, inhibition of CK1 increases NMDA-mediated EPSCs in medium spiny striatal neurons. This effect is associated with an increased phosphorylation of the NR1 and NR2B subunits of the NMDA receptor and is occluded by the phosphatase inhibitor okadaic acid. The mGluR1, but not mGluR5, subclass of metabotropic glutamate receptors uses CK1 to inhibit NMDA-mediated synaptic currents. These results provide the first evidence for a role of CK1 in the regulation of synaptic transmission in the brain.
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PMID:Physiological role for casein kinase 1 in glutamatergic synaptic transmission. 1601 21

Fragile X syndrome (FXS) has so far resisted efforts to define the basic cellular defects caused by the absence of a single protein, fragile X mental retardation protein (FMRP), because the patients have a wide variety of symptoms of varying severity. Immature-appearing dendritic spines on neurons found in FXS patients and fmr1-KO mice suggest a role for FMRP in modulating production of synaptic structural proteins. We isolated cortical synaptoneurosomes from WT and KO mice and studied MAPK pathway activation after group I metabotropic glutamate receptor (mGluR) stimulation. Here, we show that ERK in KO synaptoneurosomes is rapidly dephosphorylated upon mGluR1/5 stimulation, whereas it is phosphorylated in WT mice, suggesting that aberrant activation of phosphatases occurs in KO synapses in response to synaptic stimulation. In KO synapses, protein phosphatase 2A (PP2A) is overactivated after mGluR1 stimulation, and tyrosine phosphatase is overactivated after mGluR5 stimulation, causing the rapid deactivation of ERK. ERK activation can be restored in KO by pretreatment with phosphatase blockers; blocking of PP2A by okadaic acid could successfully restore normal ERK activation in KO synaptoneurosomes. We propose that overactivation of phosphatases in synapses may be a key deficit in FXS, which affects synaptic translation, transcription, and synaptic receptor regulation.
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PMID:Aberrant early-phase ERK inactivation impedes neuronal function in fragile X syndrome. 1833 24


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