Autophosphorylated calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) reversibly targets to and phosphorylates N-methyl-D-aspartate receptor subunit 2B (NR2B) in cerebral ischemia and reperfusion in hippocampus of rats

Fanjie Meng, Jun Guo, Quanguang Zhang, Bo Song, Guangyi Zhang

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24 Citations (Scopus)

Abstract

It has been reported that cerebral ischemia induces Thr286 autophosphorylation and translocation of CaMKIIα which targets to and phosphorylates NR2B in hippocampus of rats [Neuroscience 96 (2000) 665; J. Biol. Chem. 275 (2000) 23798]. To further illustrate the mechanisms underlying these processes, we examined the effects of ketamine (a selective antagonist of NMDA receptor), KN-62 (1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine, a selective inhibitor of CaMKII) and reperfusion on CaMKII and NMDA receptors and the interactions between these signal proteins. Firstly, our results showed that ketamine decreased the ischemia-induced autophosphorylation, translocation and the targeting of CaMKIIα to NR2B and the serine-phosphorylation of NR2B. Secondly, KN-62 also inhibited the autophosphorylation of CaMKIIα, NR2B serine-phosphorylation and the binding of CaMKIIα to NR2B but had no effect on the translocation of CaMKII. These data strongly suggest that NMDA receptor channels mediated the Ca2+-dependent activation of CaMKII and NMDA receptors surely were the substrates on membranes of active CaMKII. Thirdly, our results indicated the concomitant phosphorylation and dephosphorylation of CaMKII and NR2B following ischemia or longer reperfusion. Moreover, the dissociation of CaMKII from NR2B had the same trend as that of the return of CaMKII to cytosol. All these data imply the close relationships between CaMKII and NR2B during ischemia and reperfusion, namely, CaMKII might act as an amplifier of detrimental cellular calcium signal regulated by NMDA receptors when becoming autophosphorylated and targeting to NR2B; conversely, autophosphorylated CaMKII could modulate NMDA receptor channel properties by phosphorylating NR2B.

Original languageEnglish (US)
Pages (from-to)161-169
Number of pages9
JournalBrain Research
Volume967
Issue number1-2
DOIs
StatePublished - Mar 28 2003
Externally publishedYes

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
N-Methyl-D-Aspartate Receptors
Brain Ischemia
Reperfusion
Hippocampus
KN 62
Ischemia
Phosphorylation
Ketamine
Serine
Neurosciences

Keywords

  • Autophosphorylation
  • CaMKII
  • Cerebral ischemia
  • KN-62
  • Ketamine
  • NR2B
  • Rat
  • Serine phosphorylation
  • Translocation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

@article{dc1ed739259f45ccb1d8e6dc6195a9c1,
title = "Autophosphorylated calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) reversibly targets to and phosphorylates N-methyl-D-aspartate receptor subunit 2B (NR2B) in cerebral ischemia and reperfusion in hippocampus of rats",
abstract = "It has been reported that cerebral ischemia induces Thr286 autophosphorylation and translocation of CaMKIIα which targets to and phosphorylates NR2B in hippocampus of rats [Neuroscience 96 (2000) 665; J. Biol. Chem. 275 (2000) 23798]. To further illustrate the mechanisms underlying these processes, we examined the effects of ketamine (a selective antagonist of NMDA receptor), KN-62 (1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine, a selective inhibitor of CaMKII) and reperfusion on CaMKII and NMDA receptors and the interactions between these signal proteins. Firstly, our results showed that ketamine decreased the ischemia-induced autophosphorylation, translocation and the targeting of CaMKIIα to NR2B and the serine-phosphorylation of NR2B. Secondly, KN-62 also inhibited the autophosphorylation of CaMKIIα, NR2B serine-phosphorylation and the binding of CaMKIIα to NR2B but had no effect on the translocation of CaMKII. These data strongly suggest that NMDA receptor channels mediated the Ca2+-dependent activation of CaMKII and NMDA receptors surely were the substrates on membranes of active CaMKII. Thirdly, our results indicated the concomitant phosphorylation and dephosphorylation of CaMKII and NR2B following ischemia or longer reperfusion. Moreover, the dissociation of CaMKII from NR2B had the same trend as that of the return of CaMKII to cytosol. All these data imply the close relationships between CaMKII and NR2B during ischemia and reperfusion, namely, CaMKII might act as an amplifier of detrimental cellular calcium signal regulated by NMDA receptors when becoming autophosphorylated and targeting to NR2B; conversely, autophosphorylated CaMKII could modulate NMDA receptor channel properties by phosphorylating NR2B.",
keywords = "Autophosphorylation, CaMKII, Cerebral ischemia, KN-62, Ketamine, NR2B, Rat, Serine phosphorylation, Translocation",
author = "Fanjie Meng and Jun Guo and Quanguang Zhang and Bo Song and Guangyi Zhang",
year = "2003",
month = "3",
day = "28",
doi = "10.1016/S0006-8993(02)04267-1",
language = "English (US)",
volume = "967",
pages = "161--169",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "1-2",

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TY - JOUR

T1 - Autophosphorylated calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) reversibly targets to and phosphorylates N-methyl-D-aspartate receptor subunit 2B (NR2B) in cerebral ischemia and reperfusion in hippocampus of rats

AU - Meng, Fanjie

AU - Guo, Jun

AU - Zhang, Quanguang

AU - Song, Bo

AU - Zhang, Guangyi

PY - 2003/3/28

Y1 - 2003/3/28

N2 - It has been reported that cerebral ischemia induces Thr286 autophosphorylation and translocation of CaMKIIα which targets to and phosphorylates NR2B in hippocampus of rats [Neuroscience 96 (2000) 665; J. Biol. Chem. 275 (2000) 23798]. To further illustrate the mechanisms underlying these processes, we examined the effects of ketamine (a selective antagonist of NMDA receptor), KN-62 (1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine, a selective inhibitor of CaMKII) and reperfusion on CaMKII and NMDA receptors and the interactions between these signal proteins. Firstly, our results showed that ketamine decreased the ischemia-induced autophosphorylation, translocation and the targeting of CaMKIIα to NR2B and the serine-phosphorylation of NR2B. Secondly, KN-62 also inhibited the autophosphorylation of CaMKIIα, NR2B serine-phosphorylation and the binding of CaMKIIα to NR2B but had no effect on the translocation of CaMKII. These data strongly suggest that NMDA receptor channels mediated the Ca2+-dependent activation of CaMKII and NMDA receptors surely were the substrates on membranes of active CaMKII. Thirdly, our results indicated the concomitant phosphorylation and dephosphorylation of CaMKII and NR2B following ischemia or longer reperfusion. Moreover, the dissociation of CaMKII from NR2B had the same trend as that of the return of CaMKII to cytosol. All these data imply the close relationships between CaMKII and NR2B during ischemia and reperfusion, namely, CaMKII might act as an amplifier of detrimental cellular calcium signal regulated by NMDA receptors when becoming autophosphorylated and targeting to NR2B; conversely, autophosphorylated CaMKII could modulate NMDA receptor channel properties by phosphorylating NR2B.

AB - It has been reported that cerebral ischemia induces Thr286 autophosphorylation and translocation of CaMKIIα which targets to and phosphorylates NR2B in hippocampus of rats [Neuroscience 96 (2000) 665; J. Biol. Chem. 275 (2000) 23798]. To further illustrate the mechanisms underlying these processes, we examined the effects of ketamine (a selective antagonist of NMDA receptor), KN-62 (1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine, a selective inhibitor of CaMKII) and reperfusion on CaMKII and NMDA receptors and the interactions between these signal proteins. Firstly, our results showed that ketamine decreased the ischemia-induced autophosphorylation, translocation and the targeting of CaMKIIα to NR2B and the serine-phosphorylation of NR2B. Secondly, KN-62 also inhibited the autophosphorylation of CaMKIIα, NR2B serine-phosphorylation and the binding of CaMKIIα to NR2B but had no effect on the translocation of CaMKII. These data strongly suggest that NMDA receptor channels mediated the Ca2+-dependent activation of CaMKII and NMDA receptors surely were the substrates on membranes of active CaMKII. Thirdly, our results indicated the concomitant phosphorylation and dephosphorylation of CaMKII and NR2B following ischemia or longer reperfusion. Moreover, the dissociation of CaMKII from NR2B had the same trend as that of the return of CaMKII to cytosol. All these data imply the close relationships between CaMKII and NR2B during ischemia and reperfusion, namely, CaMKII might act as an amplifier of detrimental cellular calcium signal regulated by NMDA receptors when becoming autophosphorylated and targeting to NR2B; conversely, autophosphorylated CaMKII could modulate NMDA receptor channel properties by phosphorylating NR2B.

KW - Autophosphorylation

KW - CaMKII

KW - Cerebral ischemia

KW - KN-62

KW - Ketamine

KW - NR2B

KW - Rat

KW - Serine phosphorylation

KW - Translocation

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U2 - 10.1016/S0006-8993(02)04267-1

DO - 10.1016/S0006-8993(02)04267-1

M3 - Article

VL - 967

SP - 161

EP - 169

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 1-2

ER -