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)

Recent data on the molecular mechanism of some immunosuppressive drugs provide strong support for the fascinating postulate that CSA and FK506 work by binding to immunophilins and then, as a drug-immunophilin complex, inhibiting the calcium-activated protein phosphatase, calcineurin. This inhibition could result in an altered modification pattern of the cytoplasmic components of transcription factors, thereby disturbing their nuclear translocation, which is a prerequisite for proper IL-2 transcription. It looks as if, with the immunosuppressive microbial metabolites as molecular probes, the pieces of this complex signal transduction puzzle are starting to fit together! Once the details of the chain of events along the T-cell signaling pathways are known, the molecular structures involved will provide new tools to be used in the search for and the rational design of new and improved therapeutic agents.
Bull Mem Acad R Med Belg 1994
PMID:Molecular mechanisms of immunosuppressive agents. 753 Oct 51

Proteins belonging to the NFAT (nuclear factor of activated T cells) family of transcription factors are expressed in most immune cell types, and play a central role in the transcription of cytokine genes, such as IL-2, IL-4, IL-5, IL-13, IFN-gamma, TNF-alpha, and GM-CSF. The activity NFAT proteins is regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a target for inhibition by CsA and FK506. Recently, two different groups have described that mice lacking the NFAT1 transcription factor show an enhanced immune response, with tendency towards the development of a late Th2-like response. This review evaluates the possible role of NFAT proteins in the Th2 immune response and in the eosinophil-mediated allergic response.
Mem Inst Oswaldo Cruz 1997
PMID:Role of the cyclosporin-sensitive transcription factor NFAT1 in the allergic response. 969 27

We have found that two distinct forms of long-term depression (LTD), one dependent on the activation of NMDA receptors (NMDARs) and the other dependent on the activation of metabotropic glutamate receptors (mGluRs), coexist in pyramidal cells of the CA1 region of the hippocampus of juvenile rats (11-35 days). Both forms were pathway specific, required membrane depolarization, and were blocked by chelating postsynaptic Ca2+ with BAPTA. The mGluR-LTD, but not the NMDAR-LTD, was blocked by the T-type Ca2+ channel blocker Ni2+ and intracellular administration of a protein kinase C inhibitory peptide. In contrast, the protein phosphatase inhibitor Microcystin LR blocked NMDAR-LTD, but not mGluR-LTD. NMDAR-LTD is associated with a decrease in the size of quantal excitatory postsynaptic currents, whereas for mGluR-LTD there was no change in quantal size, but a large decrease in the frequency of events. While mGluR-LTD did not interact with NMDAR-dependent long term potentiation (LTP), NMDAR-LTD was capable of reversing LTP. Prior saturation of mGluR-LTD had no effect on NMDAR-LTD. NMDAR-LTD and mGluR-LTD thus appear to be mechanistically distinct forms of synaptic plasticity in that they share neither induction nor expression mechanisms.
Neurobiol Learn Mem
PMID:NMDA receptor-dependent and metabotropic glutamate receptor-dependent forms of long-term depression coexist in CA1 hippocampal pyramidal cells. 975 87

The activities of protein kinases and phosphatases are believed to regulate neuronal activity and synaptic plasticity in brain. Numerous in vivo and in vitro studies have shown that synaptic strength appears stable under basal conditions and during long-term potentiation (LTP) expression. This may reflect a balance between protein kinase and phosphatase activities. To provide experimental evidence for this hypothesis, and based on our knowledge that Ca2+/CaM activates protein kinases and phosphatases and that postsynaptic Ca2+/CaM signal pathways play important roles in synaptic plasticity, we examined the contribution of postsynaptic Ca(2+)-dependent protein kinases and calcineurin (CaN) in regulating synaptic strength. We show that inhibiting postsynaptic Ca2+/CaM-dependent protein kinase II (CaM-KII) and Ca2+/phospholipitidyserine-dependent protein kinase (PKC) in hippocampal CA1 neurons attenuates significantly the expression of LTP, but not basal synaptic transmission. On the other hand, the inhibition of postsynaptic CaN enhances synaptic transmission at potentiated and naive synapses, and increases significantly the magnitude of synaptic potentiation during the induction phase of LTP. These results indicate that postsynaptic CaM-KII and PKC activities are essential for maintaining LTP expression, but CaN activity limits synaptic strength at stable levels during both basal and potentiated synaptic transmission; that is, the dynamic balance between protein phosphorylation and dephosphorylation that sets physiological synaptic strength is dominated by CaN activity.
Learn Mem
PMID:The balance between postsynaptic Ca(2+)-dependent protein kinase and phosphatase activities controlling synaptic strength. 1045 87

In the CA1 region of adult guinea pig hippocampal slices, long trains of theta frequency (5 Hz) stimulation produced a small enhancement of basal synaptic transmission but depressed the strength of synaptic transmission at synapses that had recently undergone long-term potentiation (LTP). Five hertz stimulation delivered immediately prior to high-frequency stimulation also inhibited the subsequent induction of LTP. The depression of potentiated synapses by 5 Hz stimulation (depotentiation) was blocked by 2-amino-5-phosphonovalerate and was observed only during the early phases of LTP. Furthermore, the protein phosphatase inhibitors okadaic acid and calyculin A blocked both depotentiation and the ability of 5 Hz stimulation to inhibit subsequent LTP, suggesting that protein phosphatases are involved in the ability of 5 Hz stimulation to modulate synaptic plasticity in the CA1 region of the hippocampus.
Learn Mem
PMID:Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. 1046 91

Numerous studies have demonstrated roles for protein phosphorylation and for specific kinases in memory formation; however, a role for specific protein phosphatases has not been established. Previous studies using pharmacobehavioral methods to implicate protein phosphatase activity in memory formation have been unable to discriminate between protein phosphatases 1 (PP1) and 2A (PP2A), as available cell-permeable agents generally inhibit both enzyme classes. To address this difficulty the present study exploited differences in the potency of the selective phosphatase inhibitor, okadaic acid, toward PP1 and PP2A. Within the context of a temporally precise animal model of memory, developed using the day-old chick (Gallus domesticus), acute administration of various concentrations of okadaic acid was found to disrupt two temporally distinct stages of memory formation. When administered bilaterally into an area of the chick brain implicated in memory formation, concentrations of okadaic acid known to selectively inhibit PP2A in vitro disrupted memory from 50 min posttraining. Higher concentrations, reported to inhibit both PP2A and PP1 in vitro, produced significant retention deficits from 20 min posttraining. Identical temporally specific effects were also obtained by varying the concentration and time of administration of calyculin A, a phosphatase inhibitor with equal potency toward both enzyme classes. Hence, different phosphatase enzymes may contribute to different stages of the enzymatic cascade believed to underlie memory formation.
Neurobiol Learn Mem 2001 Jan
PMID:Concentration-dependent effects of protein phosphatase (PP) inhibitors implicate PP1 and PP2A in different stages of memory formation. 1112 49

Plasticity in dendritic spines may underlie learning and memory. Spinophilin, a protein enriched in dendritic spines, has the properties of a scaffolding protein and is believed to regulate actin cytoskeletal dynamics affecting dendritic spine morphology. It also binds protein phosphatase-1 (PP-1), an enzyme that regulates dendritic spine physiology. In this study, we tested the role of spinophilin in conditioned taste aversion learning (CTA) using transgenic spinophilin knockout mice. CTA is a form of associative learning in which an animal rejects a food that has been paired previously with a toxic effect (e.g., a sucrose solution paired with a malaise-inducing injection of lithium chloride). Acquisition and extinction of CTA was tested in spinophilin knockout and wild-type mice using taste solutions (sucrose or sodium chloride) or flavors (Kool-Aid) paired with moderate or high doses of LiCl (0.15 M, 20 or 40 mL/kg). When sucrose or NaCl solutions were paired with a moderate dose of LiCl, spinophilin knockout mice were unable to learn a CTA. At the higher dose, knockout mice acquired a CTA but extinguished more rapidly than wild-type mice. A more salient flavor stimulus (taste plus odor) revealed similar CTA learning at both doses of LiCl in both knockouts and wild types. Sensory processing in the knockouts appeared normal because knockout mice and wild-type mice expressed identical unconditioned taste preferences in two-bottle tests, and identical lying-on-belly responses to acute LiCl. We conclude that spinophilin is a candidate molecule required for normal CTA learning.
Learn Mem
PMID:Impaired conditioned taste aversion learning in spinophilin knockout mice. 1158 74

The perforant path projecting from the entorhinal cortex to the hippocampal dentate gyrus is a particularly vulnerable target to the early deposition of amyloid beta (Abeta) peptides in Alzheimer's brain. The authors previously showed that brief applications of Abeta at subneurotoxic concentrations suppressed the early-phase long-term potentiation (E-LTP) in rat dentate gyrus. The current study further examines the effect of Abeta on the late-phase LTP (L-LTP) in this area. Using multiple high-frequency stimulus trains, a stable L-LTP lasting for at least 3 h was induced in the medial perforant path of rat hippocampal slices. Bath application of Abeta(1-42) (0.2-1.0 microM) during the induction trains attenuated both the initial and late stages of L-LTP. On the other hand, Abeta(1-42) perfusion within the first hour following the induction primarily impaired the late stage of L-LTP, which resembled the action of the protein synthesis inhibitor emetine. Blockade of calcineurin activity with FK506 or cyclosporin A completely prevented Abeta-induced L-LTP deficits. These results suggest that Abeta(1-42) impaired both the induction and maintenance phase of dentate L-LTP through calcineurin-dependent mechanisms. In the concentration range effective for inhibiting L-LTP, Abeta(1-42) also reduced the amplitude of NMDA receptor-mediated synaptic currents in dentate granule cells via a postsynaptic mechanism. In addition, concurrent applications of Abeta(1-42) with the protein synthesis inhibitor caused no additive reduction of L-LTP, indicating a common mechanism underlying the action of both. Thus, inhibition of NMDA receptor channels and disruption of protein synthesis were two possible mechanisms contributing to Abeta-induced L-LTP impairment.
Neurobiol Learn Mem 2002 May
PMID:Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. 1199 63

The late phase of long-term potentiation (L-LTP) is correlated with some types of long-term memory, but the mechanisms by which L-LTP is modulated by prior synaptic activity are undefined. Activation of protein phosphatases by low-frequency stimulation (LFS) given before induction of L-LTP may significantly modify L-LTP. Using cellular electrophysiological recording methods in mouse hippocampal slices, we show that LFS given before induction of L-LTP inhibited L-LTP in an activity-dependent manner without affecting either basal synaptic strength or the early phase of LTP (E-LTP). This anterograde inhibitory effect of LFS was persistent, required N-methyl-D-aspartate (NMDA) receptor activation, and was blocked by inhibitors of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). These data indicate that certain patterns of LFS can activate PP1 and/or PP2A, and that long-lasting activation of these phosphatases by prior LFS can suppress the subsequent expression of L-LTP without affecting E-LTP. Because this inhibition of L-LTP is caused by prior synaptic activity that, alone, produced no net effect on synaptic efficacy, we suggest that this is a "silent" form of metaplasticity that may influence long-term information storage by modulating the capacity of synapses to express L-LTP after repeated bouts of activity.
Learn Mem
PMID:"Silent" metaplasticity of the late phase of long-term potentiation requires protein phosphatases. 1217 28

Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activities in CB1-dependent extinction of conditioned fear behavior, conditioned CB1-deficient mice (CB1(-/-)) and wild-type littermates (CB1(+/+)) were sacrificed 30 min after recall of fear memory, and activation of ERKs, AKT, and calcineurin was examined by Western blot analysis in different brain regions. As compared with CB1(+/+), the nonreinforced tone presentation 24 h after auditory-cued fear conditioning led to lower levels of phosphorylated ERKs and/or calcineurin in the basolateral amygdala complex, ventromedial prefrontal cortex, dorsal hippocampus, and ventral hippocampus of CB1(-/-). In contrast, higher levels of phosphorylated p44 ERK and calcineurin were observed in the central nucleus of the amygdala of CB1(-/-). Phosphorylation of AKT was more pronounced in the basolateral amygdala complex and the dorsal hippocampus of CB1(-/-). We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner.
Learn Mem
PMID:CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice. 1546 18


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