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)

Insulin-like growth factor-1 (IGF-1) promotes the survival of cerebellar granule neurons by enhancing calcium influx through L-type calcium channels, whereas NMDA receptor-mediated calcium influx can lead to excitotoxic death. Here we demonstrate that L and NMDA receptor channel activities differentially regulate the transcription factor C/EBPbeta to control neuronal survival. Specifically, we show that L channel-dependent calcium influx results in increased CaMKIV activity, which acts to decrease nuclear C/EBPbeta levels. Conversely, NMDA receptor-mediated influx rapidly elevates nuclear C/EBPbeta and induces excitotoxic death via activation of the calcium-dependent phosphatase, calcineurin. Moderate levels of AMPA receptor activity stimulate L channels to improve survival, whereas higher levels stimulate NMDA receptors and reduce neuronal survival, suggesting differential synaptic effects. Finally, N-type calcium channel activity reduces survival, potentially by increasing glutamate release. Together, these results show that the L-type calcium channel-dependent survival and NMDA receptor death pathways converge to regulate nuclear C/EBPbeta levels, which appears to be pivotal in these mechanisms.
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PMID:Calcium channel and NMDA receptor activities differentially regulate nuclear C/EBPbeta levels to control neuronal survival. 1292 77

In the present experiments, we used conditioned fear to study whether changes in expression or functional state of proteins known to be involved in hippocampal learning could suggest correlation with age-related memory deficits. We focused on both alterations constitutively present in the hippocampus of aged rats and alterations related to different learning responses. Our results point at the dysregulation of the phosphorylation state of CREB in the hippocampus of aged rats as a primary biochemical correlate of their impaired memory. Other proteins, known to be important for various steps of memory formation and consolidation and linked to CREB, are to some extent altered in their constitutive expression or in the response to learning in the aged hippocampus. In particular, phosphorylated CREB and Arc, a protein functionally related to CREB in memory consolidation, are both present at constitutively higher levels in the hippocampus of aged rats, but they are not susceptible to the learning-related up-regulation occurring in young adults. Two other CREB-regulated proteins involved in memory consolidation, the neurotrophin BDNF and the transcription factor C/EBPbeta, are expressed at similar levels in the hippocampus of young-adult and aged rats, but their response to conditioned fear learning appears dysregulated by aging. Calcineurin, a protein phosphatase having CREB among its substrates and whose expression negatively correlates with learning, is more expressed in the hippocampus of aged rats. However, while calcineurin expression decreases in the hippocampus of young adults after learning, no changes are observed in the hippocampus of aged, learning-impaired rats.
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PMID:Dysregulation of memory-related proteins in the hippocampus of aged rats and their relation with cognitive impairment. 1608 28

Prostaglandin F2alpha (PGF2alpha) is a potent physiological inhibitor of adipocyte differentiation, however the specific signaling pathways and molecular mechanisms involved in mediating its anti-adipogenic effects are not well understood. In the current study, we now provide evidence that PGF2alpha inhibits adipocyte differentiation via a signaling pathway that requires heterotrimeric G-protein G alpha q subunits, the elevation of the intracellular calcium concentration ([Ca2+]i), and the activation of the Ca2+/calmodulin-regulated serine/threonine phosphatase calcineurin. We show that while this pathway acts to inhibit an early step in the adipogenic cascade, it does not interfere with the initial mitotic clonal expansion phase of adipogenesis, nor does it affect either the expression, DNA binding activity or differentiation-induced phosphorylation of the early transcription factor C/EBPbeta. Instead, we find that PGF2alpha inhibits adipocyte differentiation via a calcineurin-dependent mechanism that acts to prevent the expression of the critical pro-adipogenic transcription factors PPARgamma and C/EBPalpha. Furthermore, we demonstrate that the inhibitory effects of PGF2alpha on both the expression of PPARgamma and C/EBPalpha and subsequent adipogenesis can be attenuated by treatment of preadipocytes with the histone deacetylase (HDAC) inhibitor trichostatin A. Taken together, these results indicate that PGF2alpha inhibits adipocyte differentiation via a G alpha q-Ca2+-calcineurin-dependent signaling pathway that acts to block expression of PPARgamma and C/EBPalpha by a mechanism that appears to involves an HDAC-sensitive step.
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PMID:Prostaglandin F2alpha inhibits adipocyte differentiation via a G alpha q-calcium-calcineurin-dependent signaling pathway. 1688 2

Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.
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PMID:Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging. 1805 63

Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activities are modulated in a manner that reflects the secretory demand on beta cells to integrate long- and short-term nutrient sensing information. Our studies have focused on the mechanisms of ERK1/2 activation in beta cells and on the actions of ERK1/2 that regulate beta cell function. Insulin and growth factors regulate ERK1/2 in beta cells in a largely calcium-independent manner. Nutrients and anticipatory hormones, in contrast, activate ERK1/2 in a calcium-dependent manner in these cells. We are exploring the key intermediates in these distinct activation pathways and find that calcineurin is essential for the nutrient pathway but is not essential for the growth factor pathway. Using reporter assays, heterologous reconstitution, electrophoretic mobility shift assays, Northern analysis, Q-PCR and chromatin immunoprecipitation, we have examined several genes that are regulated by ERK1/2, primarily the insulin gene and the apoptotic factor C/EBP-homologous protein (CHOP)-10 (GADD153/DDIT-3), a bZIP protein. ERK1/2-sensitive transcriptional regulators common to these two genes are C/EBP-beta and MafA. The insulin promoter is both positively and negatively regulated by glucose and other nutrients. Exposure to glucose for minutes to hours causes an increase in the rate of insulin gene transcription. In contrast, exposure to elevated glucose for 48 h or more results in inhibition of the insulin gene promoter. Both of these processes depend on ERK1/2 activity. Expression of CHOP is induced by stresses including nutrient deprivation and endoplasmic reticulum stress. CHOP gene expression, especially that regulated by nutrients, is also ERK1/2-dependent in beta cells, These studies support the hypothesis that the genes regulated by ERK1/2 and the mechanisms employed are key to maintaining normal beta cell function.
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PMID:The protein kinases ERK1/2 and their roles in pancreatic beta cells. 1817 25

Small intestinal ulceration is a frequent and potentially serious condition associated with nonselective cyclooxygenase 1/2 inhibitors (nonsteroidal anti-inflammatory drugs, NSAIDs) including diclofenac (DCF). An initial topical effect involving mitochondria has been implicated in the pathogenesis, but the exact mechanisms of NSAID-induced enteropathy are unknown. We aimed at investigating whether DCF caused enterocyte demise via the mitochondrial permeability transition (mPT) and whether inhibition of critical mPT regulators might protect the mucosa from DCF injury. Cultured enterocytes (IEC-6) exposed to DCF readily underwent mPT-mediated cell death. We then targeted mitochondrial cyclophilin D (CypD), a key regulator of the mPT, in a mouse model of NSAID enteropathy. C57BL/6J mice were treated with an ulcerogenic dose of DCF (60 mg/kg, ip), followed (+ 1 h) by a non-cholestatic dose (10 mg/kg, ip) of the CypD inhibitor, cyclosporin A (CsA). CsA greatly reduced the extent of small intestinal ulceration. To avoid potential calcineurin-mediated effects, we used the non-immunosuppressive cyclosporin analog, D-MeAla(3)-EtVal(4)-cyclosporin (Debio 025). Debio 025 similarly protected the mucosa from DCF injury. To exclude drug-drug interactions, we exposed mice genetically deficient in mitochondrial CypD (peptidyl-prolyl cis-trans isomerase F [Ppif(-/-)]) to DCF. Ppif-null mice were largely protected from the ulcerogenic effects of DCF, whereas their wild-type littermates developed typical enteropathy. Enterocyte injury was preceded by upregulation of the proapoptotic transcription factor C/EBP homologous protein (Chop). Chop-null mice were refractory to DCF enteropathy, suggesting a critical role of endoplasmic reticulum stress induced by DCF. In conclusion, mitochondrial CypD plays a key role in NSAID-induced enteropathy, lending itself as a potentially new therapeutic target for cytoprotective intervention.
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PMID:Pharmacologic targeting or genetic deletion of mitochondrial cyclophilin D protects from NSAID-induced small intestinal ulceration in mice. 2066

GM2-gangliosidosis, a subgroup of lysosomal storage disorders, is caused by deficiency of hexosaminidase activity, and comprises the closely related Tay-Sachs and Sandhoff diseases. The enzyme deficiency prevents normal metabolization of ganglioside GM2, usually resulting in progressive neurodegenerative disease. The molecular mechanisms whereby GM2 accumulation in neurons triggers neurodegeneration remain unclear. In vitro experiments, using microsomes from Sandhoff mouse model brain, showed that increase of GM2 content negatively modulates sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) (Pelled et al., 2003). Furthermore, Ca²⁺ depletion in endoplasmic reticulum (ER) triggers Unfolded Protein Response (UPR), which tends to restore homeostasis in the ER; however, if cellular damage persists, an apoptotic response is initiated. We found that ER GM2 accumulation in cultured neurons induces luminal Ca²⁺ depletion, which in turn activates PERK (protein kinase RNA [PKR]-like ER kinase), one of three UPR sensors. PERK signaling displayed biphasic activation; i.e., early upregulation of cytoprotective calcineurin (CN) and, under prolonged ER stress, enhanced expression of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Moreover, GM2 accumulation in neuronal cells induced neurite atrophy and apoptosis. Both processes were effectively modulated by treatment with the selective PERK inhibitor GSK2606414, by CN knockdown, and by CHOP knockdown. Overall, our findings demonstrate the essential role of PERK signaling pathway contributing to neurodegeneration in a model of GM2-gangliosidosis.
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PMID:Neurite atrophy and apoptosis mediated by PERK signaling after accumulation of GM2-ganglioside. 3038 74

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