Calcineurin regulation of neuronal plasticity

Groth, Rachel D.; Dunbar, Robert L.; Mermelstein, P.

doi:10.1016/j.bbrc.2003.09.002

Cited by 147 publications

(102 citation statements)

References 152 publications

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“…In contrast, lower amounts of calcium in the postsynaptic neuron will cause calmodulin to activate PP2B, leading to activation of protein phosphatase 1 and a subsequent reduction of CaMKII activity (reviewed in ref. 10). It remains to be explained, however, how calmodulin performs this dual function dependent on calcium levels.…”

mentioning

confidence: 99%

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

Stefan

Edelstein

Novère

2008

Proc. Natl. Acad. Sci. U.S.A.

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Calmodulin plays a vital role in mediating bidirectional synaptic plasticity by activating either calcium/calmodulin-dependent protein kinase II (CaMKII) or protein phosphatase 2B (PP2B) at different calcium concentrations. We propose an allosteric model for calmodulin activation, in which binding to calcium facilitates the transition between a low-affinity [tense ( T )] and a high-affinity [relaxed ( R )] state. The four calcium-binding sites are assumed to be nonidentical. The model is consistent with previously reported experimental data for calcium binding to calmodulin. It also accounts for known properties of calmodulin that have been difficult to model so far, including the activity of nonsaturated forms of calmodulin (we predict the existence of open conformations in the absence of calcium), an increase in calcium affinity once calmodulin is bound to a target, and the differential activation of CaMKII and PP2B depending on calcium concentration.

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mentioning

confidence: 99%

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

Stefan

Edelstein

Novère

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…PP2B/calcineurin is a dimeric phosphatase composed of a catalytic subunit (A) and a regulatory subunit (B) [25,55]. The catalytic subunit is activated by binding to the calcium/ calmodulin complex.…”

Section: Regulation Of Extracellular Adenosine By Phosphatase 1/2a Bmentioning

confidence: 99%

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

Rosenberg

2007

Brain Research

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We have previously demonstrated that NMDA receptor-mediated extracellular adenosine accumulation in neuronal cultures is receptor-mediated and requires calcium influx. Because protein kinase C (PKC) is a calcium-dependent enzyme, we hypothesized that activation of PKC might be involved in NMDA-mediated adenosine accumulation. PKC inhibitors however, did not block NMDA-evoked adenosine accumulation, but rather, stimulated basal adenosine accumulation. These data suggested the possibility that NMDA receptor mediated adenosine accumulation involves net dephosphorylation rather than phosphorylation of one or more substrates. Thus, inhibition of kinases would be expected to increase adenosine accumulation and inhibition of phosphatases would be expected to block adenosine accumulation. To test this hypothesis, we used the phosphatase 1/2A inhibitors calyculin A and okadaic acid. Both inhibitors significantly reduced NMDA-evoked adenosine accumulation. In contrast phosphatase 2B inhibitors did not block NMDA-evoked adenosine accumulation. These data suggest that NMDAevoked adenosine accumulation is mediated by activation of phosphatase 1/2A. We have established previously that NMDA-mediated adenosine accumulation is associated with adenosine kinase inhibition. However, adenosine kinase is not a direct substrate for phosphatase 1/2A because inhibition of phosphatase 1/2A did not abolish NMDA-evoked adenosine kinase inhibition. Okadaic acid also had no effect on NO donor-evoked adenosine accumulation, which previously has been shown to be associated with adenosine kinase inhibition. Dephosphorylation of one or more proteins other than adenosine kinase as a consequence of NMDA receptor activation might play an important role in extracellular adenosine regulation, with important consequences for the regulation of excitatory synaptic transmission, plasticity, epileptogenesis, and excitotoxicity.

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“…1,2 This protein is a heterodimer which consists of a regulatory subunit, known as calcineurin B (CNB), and a catalytic subunit, known as calcineurin A (CNA). 3 At least three isoforms have been cloned for the catalytic subunit of CNA; CNA-a, CNA-b 4 and CNA-g (also named PPP3CC).…”

Section: Introductionmentioning

confidence: 99%

“…6,7 The functional role of these CNA subunits in the brain is not clear; however, calcineurin may regulate the dopaminergic receptor signal transduction pathway 8 as well as synaptic efficiency through the NMDA receptors. 1 There are multiple behavior alterations mimicking the symptoms of schizophrenia in conditional CNB knockout mice. 9 When the knockout only occurred in the forebrain, working/episodic-like memory was impaired.…”

Section: Introductionmentioning

confidence: 99%

More evidence supports the association of PPP3CC with schizophrenia

et al. 2007

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Calcineurin is a calcium/calmodulin-dependent protein phosphatase composed of two subunits, a regulatory subunit of calcineurin B (CNB) and a catalytic subunit of calcineurin A (CNA). PPP3CC is the c isoform of CNA located at the chromosome 8p21.3 region. To evaluate the association between PPP3CC and schizophrenia in the Taiwanese population, 10 single nucleotide polymorphism (SNP) markers across the gene were genotyped by the method of MALDI-TOF in 218 schizophrenia families with at least two affected siblings. One SNP (rs2272080) located around the exon 1 untranslated region was nominally associated with schizophrenia (P = 0.024) and significantly associated with the expression of PPP3CC in lymphoblast cell line; the TT and TG genotype had significantly higher relative expression levels than the GG genotype (P = 0.0012 and 0.015, respectively). In further endophenotype stratification, the single locus of rs2272080 and the haplotypes of both two-SNP haplotype (rs7833266-rs2272080) and seven-SNP haplotype (rs2461491-rs2469758-rs2461489-rs2469770-rs2449340-rs1482337-rs2252471) showed significant associations with the subgroup of schizophrenia with deficits of the sustained attention as tested by the continuous performance test (CPT, P < 0.05) and the executive functioning as tested by the Wisconsin Card Sorting Test (WCST, P < 0.05). The results suggest that PPP3CC gene may be a true susceptibility gene for schizophrenia.

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Calcineurin regulation of neuronal plasticity

Cited by 147 publications

References 152 publications

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

An allosteric model of calmodulin explains differential activation of PP2B and CaMKII

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

More evidence supports the association of PPP3CC with schizophrenia

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