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)

Although the macrolide immunosuppressant tacrolimus (FK506) is neuroprotective in animal models of focal and global cerebral ischaemia, the mechanism of this action is not known. FK506 inhibits the protein phosphatase calcineurin, whose substrates can include nitric oxide synthase (NOS), and the neuroprotective effect of FK506 has been attributed to inhibition of NOS activity. We have examined nitric oxide-mediated cyclic guanosine monophosphate (cGMP) accumulation in neonatal rat cerebellar prisms. As expected, N-methyl-D-aspartate (NMDA) induced a rapid, concentration dependent accumulation of cGMP that was inhibited by the NMDA receptor antagonist dizocilpine (MK801) and the NOS inhibitor L-nitro-arginine methyl ester. Phosphoserine immunopositivity following NMDA exposure was increased in the presence of FK506, confirming inhibition of calcineurin. However, FK506 had no effect on NMDA-stimulated cGMP accumulation. These findings suggest that the neuroprotective effect of FK506 may be mediated by mechanisms other than increased NOS phosphorylation.
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PMID:Nitric-oxide-synthase-mediated cyclic guanosine monophosphate production in neonatal rat cerebellar prisms is resistant to calcineurin inhibition. 1195 39

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immunosuppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic and palmitic acids in cerebral cortical superfusates during four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca(2+) levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca(2+) release, significantly enhanced ischemia/reperfusion-elicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP(3)R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca(2+)-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca(2+) stores in the chain of events which lead to PLA(2) activation and FFA formation.
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PMID:Effects of immunosuppressants, calcineurin inhibition, and blockade of endoplasmic reticulum calcium channels on free fatty acid efflux from the ischemic/reperfused rat cerebral cortex. 1244 75

Depolarization has been known to play an important role in the neuronal damage that occurs following cerebral ischemia. In the present study, we investigated the roles of calmodulin (CaM) and CaM-dependent enzymes in depolarization-induced neuronal cell death. Treatment of primary cortical neurons with 10 microM veratridine, a voltage sensitive Na(+) channel activator, induced cell death as indicated by lactate dehydrogenase leakage from neurons. CaM antagonists (calmidazolium, trifluoperazine, W-7, and W-5) inhibited cell death induced by veratridine in a concentration-dependent manner. CaM kinase II (CaMKII) inhibitors (KN-62, KN-93, and myristoylated autocamtide-2 related inhibitory peptide), but not inhibitors of nitric oxide synthase or calcineurin, prevented veratridine-induced neuronal cell death. Veratridine rapidly activated CaMKII in neurons, and CaM antagonists and a CaMKII inhibitor suppressed the CaMKII activation. These results suggest that the CaM-CaMKII pathway contributes to depolarization-evoked cell death in neurons.
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PMID:Calmodulin and calmodulin-dependent kinase II mediate neuronal cell death induced by depolarization. 1254 54

It has been demonstrated that signal transducer and activator of transcription-3 (STAT3) is activated after cerebral ischemia/reperfusion (I/R) in cortex and striatum. In this study, we investigated whether STAT3 was rapidly activated in hippocampus by cerebral ischemia without reperfusion in four-vessel occlusion (4-VO) model of Sprague-Dawley (SD) rats. The results showed that tyrosine phosphorylation and DNA binding activity of STAT3 was rapidly increased by ischemia. The p-STAT3 level in cytoplasm increased 5 min after occlusion and reached a peak at 10 min following ischemia (1.7 folds vs sham) by means of immunoblotting (IB). P-STAT3 in nucleus was gradually enhanced with its peak activity occurring at 30 min of ischemia (2.3 folds vs sham). Electrophoretic mobility shift assay (EMSA) with STAT3 probe demonstrated that DNA binding activity of STAT3 in nuclear extracts increased from 5 min and peaked at 30 min of ischemia (3.2 folds vs sham). These changes were prevented by genistein (a protein tyrosine kinase inhibitor) and antioxidant N-acetyl-L-cysteine (NAC), but promoted by sodium orthovanadate (a protein phosphatase inhibitor), which were administered to the SD rats 20 min before ischemia. These results indicate that the activation of STAT3 following cerebral ischemia may be modulated by PTK/PTP, and that this pathway may be of benefit to the adaptation of the hippocampal neurons to oxidative stress.
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PMID:Activation of STAT3 induced by cerebral ischemia in rat hippocampus and its possible mechanisms. 1281 99

Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions can critically influence neuronal survival. Recent studies show that astrocyte apoptosis may contribute to pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease and Parkinson's disease. We found that incubation of cultured rat astrocytes in a Ca(2+)-containing medium after exposure to a Ca(2+)-free medium causes an increase in intracellular Ca(2+) concentration followed by apoptosis, and that NF-kappa B, reactive oxygen species, and enzymes such as calpain, xanthine oxidase, calcineurin and caspase-3 are involved in reperfusion-induced apoptosis. Furthermore, we demonstrated that heat shock protein, mitogen-activated protein/extracellular signal-regulated kinase, phosphatidylinositol-3 kinase and cyclic GMP phosphodiesterase are target molecules for anti-apoptotic drugs. This review summarizes (1) astrocytic functions in neuroprotection, (2) current evidence of astrocyte apoptosis in both in vitro and in vivo studies including its molecular pathways such as Ca(2+) overload, oxidative stress, NF-kappa B activation, mitochondrial dysfunction, endoplasmic reticulum stress, and protease activation, and (3) several drugs preventing astrocyte apoptosis. As a whole, this article provides new insights into the potential role of astrocytes as targets for neuroprotection. In addition, the advance in the knowledge of molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders.
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PMID:Astrocyte apoptosis: implications for neuroprotection. 1506 28

Accumulating evidence indicates that the mitochondrial cell-death pathway, which involves the release of cytochrome c from mitochondria, participates in neuronal cell death after transient cerebral ischemia. However, the upstream events, that induce cytochrome c release after transient global ischemia are not fully understood. Bad is a pro-apoptotic member of the bcl-2 gene family that promotes apoptosis by binding to and inhibiting functions of anti-apoptotic proteins Bcl-2 and Bcl-xL. We investigated the effects of transient (15 min) global ischemia on the intracellular localization of Bad and the interaction of Bad with calcineurin, Akt or Bcl-xL in the vulnerable CA1 and resistant CA3/dentate gyrus of the hippocampus. Immunoblotting analysis revealed that the amount of Bad in mitochondria significantly increased after ischemia. Co-immunoprecipitation studies showed decreased interactions of Bad with Akt and calcineurin in the cytosol and increased binding with Bcl-xL in the mitochondrial fraction of hippocampal CA1, but not in the CA3/dentate gyrus region. Further, we examined the effect of recombinant Bad on the cytochrome c release from isolated mitochondria. Treatment with both recombinant Bad and calcium, but not with recombinant Bad alone, induced cytochrome c release. These results suggest that changes in localization and complex formation by Bad are, at least in part, involved in the vulnerability of cells after transient global ischemia.
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PMID:Altered Bad localization and interaction between Bad and Bcl-xL in the hippocampus after transient global ischemia. 1512 May 93

Oxidative stress after cerebral ischemia and reperfusion activates extracellular signal-regulated kinases (ERK) in brain. However, the mechanism of this activation has not been elucidated. We have previously reported that in an in vitro model of oxidative stress in immature cortical neuronal cultures, the inhibition of ERK phosphatase activity contributes to ERK1/2 activation and subsequent neuronal toxicity. This study examined whether ERK activation was associated with altered activity of ERK phosphatases in a rat cardiac arrest model. Rats in experimental groups were subjected to asphyxial cardiac arrest for 8 min and then resuscitated for 30 min. Significant ERK activation was detected in both cortex and hippocampus following ischemia/reperfusion by immunoblotting. ERK phosphatase activity was reversibly inhibited in cerebral cortex but not affected in hippocampus following ischemia/reperfusion. MEK1/2 was activated in both cerebral cortex and hippocampus following ischemia/reperfusion. Using a specific inhibitor of protein phosphatase 2A (PP2A), okadaic acid (OA), we have identified PP2A to be the major ERK phosphatase that is responsible for regulating ERK activation in ischemic brain tissues. Orthovanadate inhibited ERK phosphatase activity in brain tissues, suggesting that tyrosine phosphatases and dual specificity phosphatases may also contribute to the ERK phosphatase activity in brain tissues. Together, these data implicate ERK phosphatase in the regulation of ERK activation in distinct brain regions following global ischemia.
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PMID:Different mechanisms account for extracellular-signal regulated kinase activation in distinct brain regions following global ischemia and reperfusion. 1720 79

Ischemic brain injury is a critical condition in the management of patients during anesthesia and intensive care. It is not rare that pathological conditions such as cerebral ischemia, head trauma and low oxygen result in marked impairment of cerebral function, even if the patient's life is saved. We sometimes encounter sudden changes in a patient's condition not only during anesthesia, but also in intensive care unit with transient low-oxygen and ischemic conditions accompanying serious shock. We have been studying the mechanisms to counteract pathological conditions leading to neuronal cell death that have been exposed to such emergency conditions, and to discover therapeutic methods to minimize the brain damage after insult. With advances in the understanding of the mechanism of neuronal cell death, technology in intensive care for salvaging neuronal cell that are at the brink of death and for recovery of brain function has progressed. However, a breakthrough has not been achieved in the development of effective therapy. Protection of the brain from terminal impairment and preservation of function will be an important issue. To achieve this goal, it is critical to clarify the susceptible mechanisms causing ischemic brain damage. This report discusses the importance of the calcineurin/immunophilin signal transduction mechanism as a new mechanism that is involved in the induction of ischemic brain damage and refers the status-quo of cerebral protection by drug therapy.
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PMID:[Molecular mechanism of ischemic brain injuries and perspectives of drug therapies for neuroprotection]. 1736 13

The immunosuppressant cyclosporin A (CsA) has been shown to exert potent neuroprotective effects, possibly via the inhibition of calcineurin and mitochondrial permeability transition pore formation. Here, we investigated the neuroprotective profile of a novel derivative of CsA, FR901459, by evaluating its effects against in vitro mitochondrial damage and in vivo brain damage in transient global or focal cerebral ischemia models, in comparison with those of CsA. Efficacy of calcineurin inhibition was estimated from its immunosuppressive effect on the mixed lymphocyte reaction. Results showed that the immunosuppressive effect of FR901459 was approximately 7-fold less potent than that of CsA. In contrast, FR901459 suppressed Ca(2+)-induced mitochondrial swelling measured in isolated liver mitochondria with greater potency than CsA. Further, FR901459 showed approximately 30-fold greater neuroprotective potency than CsA against neuronal cell damage induced by thapsigargin in SH-SY5Y cells. In a transient global cerebral ischemia model in gerbils, FR901459 showed the dose-dependent suppression of neuronal cell death, while FR901459 was less efficacious than CsA. In a rat transient focal ischemia model, FR901459 tended to reduce brain damage on both intravenous injection as well as intracerebroventricular infusion, but with less efficacy than CsA which significantly reduced the damage. These findings suggest that FR901459 exerts a potent neuroprotective effect by inhibiting mitochondrial damage in vitro, but that in in vivo transient cerebral ischemia, its immunosuppressive component which possibly acts via the inhibition of calcineurin may play a more important role in attenuating brain damage than its inhibitory effect against mitochondrial damage.
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PMID:Neuroprotective efficacy of FR901459, a novel derivative of cyclosporin A, in in vitro mitochondrial damage and in vivo transient cerebral ischemia models. 1739 53

Intracellular calcium is a powerful secondary messenger that affects a number of calcium sensors, including calpain, a Ca2+-dependent cysteine protease, and calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. Maintenance of low basal levels of intracellular calcium allows for the tightly regulated physiological activation of these proteins, which is crucial to a wide variety of cellular processes, such as fertilization, proliferation, development, learning, and memory. Deregulation of calpain and calcineurin has been implicated in the pathogenesis of several disorders, including hypertension, heart disease, diabetes, cerebral ischemia, and Alzheimer's disease. Recent studies have demonstrated an interplay between calpain and calcineurin, in which calpain can directly regulate calcineurin activity through proteolysis in glutamate-stimulated neurons in culture and in vivo. The calpain-mediated proteolytic cleavage of calcineurin increases phosphatase activity, which promotes caspase-mediated neuronal cell death. Thus, the activation of the calpain-calcineurin pathway could contribute to calcium-dependent disorders, especially those associated with Alzheimer's disease and myocardial hypertrophy. Here, we focus briefly on recent advances in revealing the structural and functional properties of these 2 calcium-activated proteins, as well as on the interplay between the 2, in an effort to understand how calpain-calcineurin signaling may relate to the pathogenesis of calcium- dependent disorders.
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PMID:Calpain-calcineurin signaling in the pathogenesis of calcium-dependent disorder. 1759 48


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