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

A discontinuous structure-activity relationship signaled a change in mode of action and led to the discovery of a possible novel metabolic activation mechanism. The toxicity of the herbicide endothal (exo,exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid) to mice (ip LD50 = 14 mg/kg) is attributed to the inhibition of protein phosphatase 2A (PP2A) at the cantharidin binding site. The potency is reduced by the introduction of a 2,3- or 5,6-double bond. Surprisingly, high toxicity (ip LD50's = 15-50 mg/kg) is restored in oxabicyclohepta-2(3),5(6)-dienes substituted in the 2- and 3-positions with bis(methyl carboxylate), bis(ethyl carboxylate), and diethyl phosphonate/ethyl carboxylate, whereas the dicarboxylic acid, bis(tert-butyl carboxylate), and bis(dimethyl phosphonate) are inactive. The diene adducts do not inhibit the cantharidin binding site of PP2A. Two observations provided an alternative working hypothesis that the active but not the inactive diene adducts are protoxicants: GC analyses revealed that selected bicyclic dienes readily undergo thermal dissociation by retro-Diels-Alder reactions to liberate disubstituted acetylenes; the liberated acetylenes have mouse ip LD50's of 8-25 mg/kg. Apparent exceptions to this hypothesis are that bicyclic dienes with bis(tert-butyl carboxylate) and bis(dimethyl phosphonate) substituents are not toxic, yet their corresponding acetylenes are quite toxic. These apparent anomalies are resolved by finding that only the toxic bicyclic dienes readily react with albumin and 4-nitrobenzenethiol and that their low-toxicity analogs are much less reactive. Albumin can be replaced by hemoglobin but not by myoglobin or chymotrypsin in reaction with a bicyclic diene indicating the importance of the free thiol group. Diethyl oxabicycloheptadienedicarboxylate readily reacts with GSH to give two products, which are also formed from the corresponding acetylene, identified as the cis and trans isomers of the GSH-acetylene conjugate. This is the first proposal, to our knowledge, that a retro-Diels-Alder-type reaction is involved in the metabolic activation of a toxicant.
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PMID:Retro-Diels-Alder reaction: possible involvement in the metabolic activation of 7-oxabicyclo[2.2.1]hepta-2(3),5(6)-diene-2,3-dicarboxylates and a phosphonate analog. 892 98

Hyperammonemia is considered the main cause for the neurological alterations found in hepatic failure. However, the mechanisms by which high ammonia levels impair cerebral function are not well understood. It has been shown that chronic hyperammonemia impairs signal transduction pathways associated with NMDA receptors and also alters phosphorylation of some neuronal proteins. The aim of the present work was to analyze the effects of chronic exposure to ammonia on phosphorylation of microtubule-associated protein 2 (MAP-2) in intact neurons in culture and to assess whether modulation of MAP-2 phosphorylation by glutamate receptor-associated transduction pathways is altered in neurons chronically exposed to ammonia. It is shown that chronic exposure to ammonia increases basal phosphorylation of MAP-2 by approximately 70%. This effect seems to be due to a decreased tonic activation of NMDA receptors and of calcineurin. Chronic exposure to ammonia also alters the modulation of MAP-2 phosphorylation by NMDA receptors and metabotropic glutamate receptors. In neurons exposed to ammonia, treatment with NMDA for 30 min induced a significant decrease in phosphorylation of MAP-2. Activation of metabotropic glutamate receptors with (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid significantly increased phosphorylation of MAP-2 in control neurons, whereas in neurons exposed to ammonia the response was the opposite, with 1-aminocyclopentane-1,3-dicarboxylic acid inducing a dephosphorylation of MAP-2. These results indicate that ammonia alters significantly signal transduction pathways associated with different types of glutamate receptors. This would lead therefore to significant alterations in glutamatergic neurotransmission, which would contribute to the neurological alterations found in hyperammonemia and in hepatic encephalopathy.
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PMID:Chronic exposure to ammonia alters pathways modulating phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture. 1058 18

Protein tyrosine phosphatase 1B (PTP1B) attenuates insulin signaling by catalyzing dephosphorylation of insulin receptors (IR) and is an attractive target of potential new drugs for treating the insulin resistance that is central to type II diabetes. Several analogues of cholecystokinin(26)(-)(33) (CCK-8) were found to be surprisingly potent inhibitors of PTP1B, and a common N-terminal tripeptide, N-acetyl-Asp-Tyr(SO(3)H)-Nle-, was shown to be necessary and sufficient for inhibition. This tripeptide was modified to reduce size and peptide character, and to replace the metabolically unstable sulfotyrosyl group. This led to the discovery of a novel phosphotyrosine bioisostere, 2-carboxymethoxybenzoic acid, and to analogues that were >100-fold more potent than the CCK-8 analogues and >10-fold selective for PTP1B over two other PTP enzymes (LAR and SHP-2), a dual specificity phosphatase (cdc25b), and a serine/threonine phosphatase (calcineurin). These inhibitors disrupted the binding of PTP1B to activated IR in vitro and prevented the loss of tyrosine kinase (IRTK) activity that accompanied PTP1B-catalyzed dephosphorylation of IR. Introduction of these poorly cell permeant inhibitors into insulin-treated cells by microinjection (oocytes) or by esterification to more lipophilic proinhibitors (3T3-L1 adipocytes and L6 myocytes) resulted in increased potency, but not efficacy, of insulin. In some instances, PTP1B inhibitors were insulin-mimetic, suggesting that in unstimulated cells PTP1B may suppress basal IRTK activity. X-ray crystallography of PTP1B-inhibitor complexes revealed that binding of an inhibitor incorporating phenyl-O-malonic acid as a phosphotyrosine bioisostere occurred with the mobile WPD loop in the open conformation, while a closely related inhibitor with a 2-carboxymethoxybenzoic acid bioisostere bound with the WPD loop closed, perhaps accounting for its superior potency. These CCK-derived peptidomimetic inhibitors of PTP1B represent a novel template for further development of potent, selective inhibitors, and their cell activity further justifies the selection of PTP1B as a therapeutic target.
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PMID:Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action. 1134 29

The calcium-dependent transcription factor NFATc3, which is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors, is critical for embryonic vascular development and differentiation. Despite its potential importance, nothing is known about NFATc3 regulation in the brain microcirculation. In the present study, we sought to investigate the role that glutamate, possibly through astrocytic communication, plays in the control of NFATc3 regulation in pericytes from parenchymal microvessels. Coronal cortical slices from neonatal rats were subjected to electrical field stimulation or were treated with the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD). NFATc3, glial fibrillary acidic protein (an astrocyte-specific marker), and platelet-derived growth factor-beta-receptor (a pericyte-specific marker) were detected by immunofluorescence. Electrical field stimulation induced NFATc3 nuclear accumulation in pericytes. This response was dependent on neuronal activity and group I metabotropic glutamate receptor (mGluR) activation. In addition, t-ACPD significantly increased NFATc3 nuclear accumulation in both astrocytes and pericytes. NFATc3 nuclear accumulation in pericytes was prevented when astrocytic function was abolished with the gliotoxin L-alpha-aminoadipate or by the inhibition of calcineurin, cyclooxygenase, and nitric oxide synthase. This is the first study to report NFATc3 expression in pericytes from parenchymal microvessels and in astrocytes from native tissue. Our results suggest a model by which glutamate, via mGluR activation, may regulate gene transcription in pluripotent vascular pericytes.
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PMID:Activity-dependent NFATc3 nuclear accumulation in pericytes from cortical parenchymal microvessels. 1788 10