Humanin protects cortical neurons from calyculin A-induced neurotoxicities by increasing PP2A activity and SOD

Background Anesthetics may interact with ionotropic glutamate receptors to produce some of their biologic actions. Cellular studies reveal that the ionotropic glutamate receptors, N-methyl-D-aspartate receptors (NMDARs), can be phosphorylated on their NR1 subunits at the C-terminal serine residues, which is a major mechanism for the regulation of NMDAR functions. It is currently unknown whether anesthetics have any modulatory effects on NMDAR NR1 subunit phosphorylation. Methods The possible effect of a general anesthetic propofol on phosphorylation of NR1 subunits at serine 897 (pNR1S897) and 896 (pNR1S896) was detected in cultured rat cortical neurons. Results Propofol consistently reduced basal levels of pNR1S897 and pNR1S896 in a concentration-dependent manner. This reduction was rapid as the reliable reduction of pNR1S896 developed 1 min after propofol administration. Pretreatment of cultures with the protein phosphatase 2A inhibitors okadaic acid or calyculin A blocked the effect of propofol on the NR1 phosphorylation, whereas okadaic acid or calyculin A alone did not alter basal pNR1S897 and pNR1S896 levels. In addition, propofol decreased tyrosine phosphorylation of protein phosphatase 2A at tyrosine 307, resulting in an increase in protein phosphatase 2A activity. In the presence of propofol, the NMDAR agonist-induced intracellular Ca2+ increase was impaired in neurons with dephosphorylated NR1 subunits. Conclusions Together, these data indicate an inhibitory effect of a general anesthetic propofol on NMDAR NR1 subunit phosphorylation in neurons. This inhibition was mediated through a signaling mechanism involving activation of protein phosphatase 2A.

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Synergetic Activation of p38 Mitogen-Activated Protein Kinase and Caspase-3-Like Proteases for Execution of Calyculin A-Induced Apoptosis but Not N-Methyl-d-Aspartate-Induced Necrosis in Mouse Cortical Neurons

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2000.0742455.x ◽

2002 ◽

Vol 74 (6) ◽

pp. 2455-2461 ◽

Cited By ~ 32

Author(s):

Hyuk Wan Ko ◽

Kong Sook Han ◽

Eun Young Kim ◽

Bo Rum Ryu ◽

Won Joo Yoon ◽

...

Keyword(s):

Protein Kinase ◽

Cortical Neurons ◽

Caspase 3 ◽

Mitogen Activated Protein Kinase ◽

Calyculin A ◽

Mitogen Activated Protein ◽

Induced Apoptosis

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New Treatment for Alzheimer’s Disease, Kamikihito, Reverses Amyloid-β-Induced Progression of Tau Phosphorylation and Axonal Atrophy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/706487 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Hidetoshi Watari ◽

Yutaka Shimada ◽

Chihiro Tohda

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Neurons ◽

Axonal Degeneration ◽

Amyloid Β ◽

Tau Phosphorylation ◽

Axonal Atrophy ◽

Pp2a Activity

Aims.We previously reported that kamikihito (KKT), a traditional Japanese medicine, improved memory impairment and reversed the degeneration of axons in the 5XFAD mouse model of Alzheimer’s disease (AD). However, the mechanism underlying the effects of KKT remained unknown. The aim of the present study was to investigate the mechanism by which KKT reverses the progression of axonal degeneration.Methods.Primary cultured cortical neurons were treated with amyloid beta (Aβ) fragment comprising amino acid residues (25–35) (10 μM) in anin vitroAD model. KKT (10 μg/mL) was administered to the cells before or after Aβtreatment. The effects of KKT on Aβ-induced tau phosphorylation, axonal atrophy, and protein phosphatase 2A (PP2A) activity were investigated. We also performed anin vivoassay in which KKT (500 mg/kg/day) was administered to 5XFAD mice once a day for 15 days. Cerebral cortex homogenates were used to measure PP2A activity.Results.KKT improved Aβ-induced tau phosphorylation and axonal atrophy after they had already progressed. In addition, KKT increased PP2A activityin vitroandin vivo.Conclusions.KKT reversed the progression of Aβ-induced axonal degeneration. KKT reversed axonal degeneration at least in part through its role as an exogenous PP2A stimulator.

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Phosphorylation and activation of phosphodiesterase type 3B (PDE3B) in adipocytes in response to serine/threonine phosphatase inhibitors: deactivation of PDE3B in vitro by protein phosphatase type 2A

Biochemical Journal ◽

10.1042/bj3410839 ◽

1999 ◽

Vol 341 (3) ◽

pp. 839-845 ◽

Cited By ~ 24

Author(s):

Svante RESJÖ ◽

Alina OKNIANSKA ◽

Stanislaw ZOLNIEROWICZ ◽

Vincent MANGANIELLO ◽

Eva DEGERMAN

Keyword(s):

Cyclosporin A ◽

Okadaic Acid ◽

Protein Phosphatase ◽

Calyculin A ◽

Phosphatase Inhibitors ◽

Pp2a Activity ◽

Phosphodiesterase Type ◽

Fold Activation ◽

Protein Phosphatase Type

Phosphodiesterase type 3B (PDE3B) has been shown to be activated and phosphorylated in response to insulin and hormones that increase cAMP. In order to study serine/threonine protein phosphatases involved in the regulation of rat adipocyte PDE3B, we investigated the phosphorylation and activation of PDE3B in vivoin response to phosphatase inhibitors and the dephosphorylation and deactivation of PDE3B in vitroby phosphatases purified from rat adipocyte homogenates. Okadaic acid and calyculin A induced dose- and time-dependent activation of PDE3B. Maximal effects were obtained after 30 min using 1 μM okadaic acid (1.8-fold activation) and 300 nM calyculin A (4-fold activation), respectively. Tautomycin and cyclosporin A did not induce activation of PDE3B. Incubation of adipocytes with 300 nM calyculin A inhibited protein phosphatase (PP) 1 and PP2A completely. Okadaic acid (1 μM) reduced PP2A activity by approx. 50% but did not affect PP1 activity, and 1 μM tautomycin reduced PP1 activity by approx. 60% but PP2A activity by only 11%. This indicates an important role for PP2A in the regulation of PDE3B. Furthermore, rat adipocyte PDE3B phosphatase activity co-purified with PP2A but not with PP1 during MonoQ chromatography. As compared with insulin, okadaic acid and calyculin A induced phosphorylation of PDE3B by 2.8- and 14-fold respectively, whereas tautomycin and cyclosporin A had no effect. Both calyculin A and okadaic acid induced phosphorylation on serine 302, the site known to be phosphorylated on PDE3B in response to insulin and isoproterenol (isoprenaline), as well as on sites not identified previously. In summary, PP2A seems to be involved in the regulation of PDE3B in vivoand can act as a PDE3B phosphatase in vitro. In comparison with insulin, calyculin A induced a dramatic activation of PDE3B and both calyculin A and okadaic acid induced phosphorylation on additional sites, which could have a role in signalling pathways not yet identified.

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