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)

Calcium has now become important as a regulator of gene expression. Cerebellar granule cells developing in culture undergo early apoptosis unless their calcium is permitted to increase, e.g., by depolarizing their plasma membrane. The increase is kept within controlled limits by changing the pattern of transcription of calcium transporters: The IP(3) channel (but not the ryanodine channel) becomes strongly up-regulated after some days in culture in a reaction which is controlled by calcineurin. Two plasma membrane calcium pumps (isoforms PMCA2 and PMCA3) also become strongly up-regulated after some days; one (PMCA1) experiences instead a splicing switch which up-regulates a truncated variant of the isoform. By contrast, one splicing variant of the isoform PMCA4 and one of the Na/Ca exchangers of the plasma membrane (NCX2) become very rapidly down-regulated: Their down-regulation is also controlled by calcineurin. The altered pattern of Ca(2+) transporter expression is likely to reflect development-linked changes in the demands for calcium signaling in different domains of the neuronal cell.
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PMID:Calcium controls the transcription of its own transporters and channels in developing neurons. 1060 99

The Na(+)/Ca(2+) exchanger (NCX) and the plasma membrane Ca(2+)-ATPase export Ca(2+) from the cytosol to the extracellular space. Three NCX genes (NCX1, NCX2, and NCX3), encoding proteins with very similar properties, are expressed at different levels in tissues. Essentially, no information is available on the mechanisms that regulate their expression. Specific antibodies have been prepared and used to explore the expression of NCX1 and NCX2 in rat cerebellum. The expression of NCX2 became strongly up-regulated during development, whereas comparatively minor effects were seen for NCX1. This was also observed in cultured granule cells induced to mature in physiological concentrations of potassium. By contrast, higher K(+) concentrations, which induce partial depolarization of the plasma membrane and promote the influx of Ca(2+), caused the complete disappearance of NCX2. Reverse transcription-polymerase chain reaction analysis showed that the process occurred at the transcriptional level and depended on the activation of the Ca(2+) calmodulin-dependent protein phosphatase, calcineurin. The NCX1 and NCX3 genes were also affected by the depolarizing treatment: the transcription of the latter became up-regulated, and the pattern of expression of the splice variants of the former changed. The effects on the NCX1 and NCX3 genes were calcineurin-independent.
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PMID:Calcineurin controls the transcription of Na+/Ca2+ exchanger isoforms in developing cerebellar neurons. 1076 88

Na⁺/Ca²⁺ exchangers (NCXs) are expressed primarily in the plasma membrane of most cell types, where they mediate electrogenic exchange of one Ca²⁺ for three Na⁺ ions, depending on Ca²⁺ and Na⁺ electrochemical gradients across the membrane. Three mammalian NCX isoforms (NCX1, NCX2, and NCX3) are each encoded by a distinct gene. Here, we report that NCX2 and NCX3 protein and mRNA levels are relatively reduced in hippocampal CA1 of APP23 and APP-KI mice. Likewise, NCX2^+/- or NCX3^+/- mice exhibited impaired hippocampal LTP and memory-related behaviors. Moreover, relative to controls, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in NCX2^+/- mouse hippocampus but increased in hippocampus of NCX3^+/- mice. NCX2 or NCX3 heterozygotes displayed impaired maintenance of hippocampal LTP, a phenotype that in NCX2^+/- mice was correlated with elevated calcineurin activity and rescued by treatment with the calcineurin (CaN) inhibitor FK506. Likewise, FK506 treatment significantly restored impaired hippocampal LTP in APP-KI mice. Moreover, Ca²⁺ clearance after depolarization following high frequency stimulation was slightly delayed in hippocampal CA1 regions of NCX2^+/- mice. Electron microscopy revealed relatively decreased synaptic density in CA1 of NCX2^+/- mice, while the number of spines with perforated synapses in CA1 significantly increased in NCX3^+/- mice. We conclude that memory impairment seen in NCX2^+/- and NCX3^+/- mice reflect dysregulated hippocampal CaMKII activity, which alters dendritic spine morphology, findings with implications for memory deficits seen in Alzheimer's disease model mice.
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PMID:Reduced expression of Na⁺/Ca²⁺ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice. 2927 51

Na⁺/Ca²⁺ exchanger (NCX) is mainly expressed in the plasma membrane and mediates electrogenical exchange of one Ca²⁺ for three Na⁺, depending on the electrochemical gradients across the plasma membrane. NCX has three different isoforms (NCX1, NCX2, NCX3) encoded by distinct genes in mammals. Here, we report that NCX2 and NCX3 protein levels are relatively reduced in hippocampal CA1 of Alzheimer's disease model mice. Likewise, NCX2^+/- or NCX3^+/- mice exhibited impaired hippocampal LTP and memory-related behaviors. In immunoblot analyses, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in hippocampal CA1 of NCX2^+/- mice compared to wild-type mice. By contrast, NCX2^+/- mice was correlated with elevated calcineurin (CaN) activity and rescued by treatment with the calcineurin inhibitor FK506. Taken together, the imbalance of CaMKII and CaN activities with concomitant LTP impairment likely accounts for the learning disability observed in NCX2^+/- mice.
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PMID:[Dysfunction of Na⁺/Ca²⁺ exchangers is associated with cognitive decline in Alzheimer's disease]. 3053 Nov 1

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