Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated τ by neuroleptics

Chen, Gong; Shaikh, Sadia; Grundke‐Iqbal, Inge; Iqbal, Khalid

doi:10.1016/s0006-8993(96)00904-3

Cited by 43 publications

(24 citation statements)

References 37 publications

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“…myosin light chain kinase, phosphodiesterase, calcineurin, etc. (45)(46)(47)(48). Previous reports showed that TFP abolishes nNOS but not iNOS activity, which is confirmed herein (49 -51).…”

Section: Discussionsupporting

confidence: 90%

Calmodulin-dependent Regulation of Inducible and Neuronal Nitric-oxide Synthase

Lee

Stull

1998

Journal of Biological Chemistry

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Neuronal and endothelial nitric-oxide synthases depend upon Ca 2؉ /calmodulin for activation, whereas the activity of the inducible nitric-oxide synthase is Ca 2؉ -independent, presumably due to tightly bound calmodulin. To study these different mechanisms, a series of chimeras derived from neuronal and inducible nitricoxide synthases were analyzed. Chimeras containing only the oxygenase domain, calmodulin-binding region, or reductase domain of inducible nitric-oxide synthase did not confer significant Ca 2؉ -independent activity. However, each chimera was more sensitive to Ca 2؉ than the neuronal isoform. The calmodulin-binding region of inducible nitric-oxide synthase with either its oxygenase or reductase domains resulted in significant, but not total, Ca 2؉ -independent activity. Co-immunoprecipitation experiments showed no calmodulin associated with the former chimera in the absence of Ca 2؉. Trifluoperazine also inhibited this chimera in the absence of Ca 2؉ . The combined interactions of calmodulin bound to inducible nitric-oxide synthase calmodulin-binding region with the oxygenase domain may be weaker than with the reductase domain. Thus, Ca 2؉ -independent activity of inducible nitric-oxide synthase appears to result from the concerted interactions of calmodulin with both the oxygenase and reductase domains in addition to the canonical calmodulin-binding region. The neuronal isoform is not regulated by a unique autoinhibitory element in its reductase domain.

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Section: Discussionsupporting

confidence: 90%

Calmodulin-dependent Regulation of Inducible and Neuronal Nitric-oxide Synthase

Lee

Stull

1998

Journal of Biological Chemistry

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“…terminated, and the released 32 P i was determined by Cerenkov counting after separation from 32 P-tau by ascending paper chromatography, as described previously (31). (TABLE ONE).…”

Section: Mass Spectrometry (Ms)-mentioning

confidence: 99%

Truncation and Activation of Calcineurin A by Calpain I in Alzheimer Disease Brain

Liu

Grundke‐Iqbal

Iqbal

et al. 2005

Journal of Biological Chemistry

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150

142

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A disturbance of calcium homeostasis is believed to play an important role in the neurodegeneration of the brains of Alzheimer disease (AD) patients, but the molecular pathways by which it contributes to the disease are not well understood. Here we studied the activation of two major Ca 2؉ -regulated brain proteins, calpain and calcineurin, in AD brain. We found that calpain I is activated, which in turn cleaves and activates calcineurin in AD brain. Mass spectrometric analysis indicated that the cleavage of calcineurin by calpain I is at lysine 501, a position C-terminal to the autoinhibitory domain, which produces a 57-kDa truncated form. The 57-kDa calcineurin maintains its Ca 2؉ /calmodulin dependence of the phosphatase activity, but the phosphatase activity is remarkably activated upon truncation. The cleavage and activation of calcineurin correlate to the number of neurofibrillary tangles in human brains. These findings suggest that the overactivation of calpain I and calcineurin may mediate the role of calcium homeostatic disturbance in the neurodegeneration of AD.

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“…Trifluoperazine and chlorpromazine inhibit Ù dephosphorylation by PP2B through antagonizing calmodulin or directly interacting with PP2B. The inhibition of the dephosphorylation of AD P-Ù by neuroleptics raises the intriguing possibility that the chronic use of these drugs might contribute to neurofibrillary degeneration in schizophrenic and AD patients [65].…”

Section: Pps and Microtubule-associated Proteinmentioning

confidence: 99%

Role of Serine/Threonine Protein Phosphatase in Alzheimer’s Disease

Tian¹,

Wang²

2002

Neurosignals

143

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Accumulating evidence indicates that serine/threonine (Ser/Thr) protein phosphatases (PPs), such as PP1, PP2A and PP2B, participate in the neurodegenerative progress in Alzheimer’s disease (AD). The general characteristics and pathologic changes of PP1, PP2A and PP2B in AD, and their relations with microtubule-associated proteins, focusing mainly on τ protein, neurofilament (NF), amyloid precursor protein (APP) processing and synaptic plasticity are discussed. Deriving novel insight into the particular topic will attract greater attention to more active investigation and effective therapeutic intervention in the future.

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Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated τ by neuroleptics

Cited by 43 publications

References 37 publications

Calmodulin-dependent Regulation of Inducible and Neuronal Nitric-oxide Synthase

Calmodulin-dependent Regulation of Inducible and Neuronal Nitric-oxide Synthase

Truncation and Activation of Calcineurin A by Calpain I in Alzheimer Disease Brain

Role of Serine/Threonine Protein Phosphatase in Alzheimer’s Disease

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