Transient ischemia enhances tyrosine phosphorylation and binding of the NMDA receptor to the Src homology 2 domain of phosphatidylinositol 3‐kinase in the rat hippocampus

2014

J Pharmacol Sci

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Cerebral ischemiaThe pathophysiologic alterations are not the same for all cells in the ischemic brain. The progress of ischemic damage is determined by several factors including the duration of the ischemic episode and the properties of the affected cells (1, 2). An interruption in cerebral blood flow, which limits oxygen and glucose, causes energy depletion, leads to a disturbance in ionic gradients, and thereby a collapse of the membrane potential of neuronal cells. The subsequent membrane depolarization induces a marked increase in the release of neurotransmitters such as excitatory amino acids. Furthermore, energy failure impairs re-uptake of the excitatory neurotransmitters by the high-affinity transporters on the surrounding Protein Tyrosine Phosphorylation in the Ischemic BrainNorio Takagi 1, * Hachioji, Tokyo 192-0392, Japan Received March 30, 2014; Accepted May 26, 2014 Abstract. Cerebral ischemia, a pathological condition in which brain tissue experiences a shortage of cerebral blood flow, is associated with cerebrovascular disease, brain trauma, epilepsy, and cardiac arrest. A reduction in blood flow leaves the brain tissue unsupplied with oxygen and glucose, thus leading to cell death in the ischemic core as well as subsequent peripheral injury in the penumbra. Neurons in the penumbra, where reperfusion occurs, are functionally inactive but still viable. Many biochemical changes, which may lead to neuronal cell death, thereby induce dysfunction of the central nervous system. However, the mechanisms responsible for ischemic stroke-induced cell damage remain to be determined. Protein phosphorylation has been implicated in the regulation of diverse cellular responses in the brain. Initially, tyrosine phosphorylation was considered to be involved in the regulation of cell growth and development. In addition, a variety of synaptic and cellular functions mediated by tyrosine phosphorylation in the brain were found to be associated with relatively high levels of protein tyrosine kinase activity. However, the involvement of this protein tyrosine kinase activity in ischemic cell death is still not fully understood. This review summarizes recent advances dealing with the possible implications of protein tyrosine phosphorylation in the ischemic brain.

Section: Tyrosine Phosphorylation Of Glutamate Receptors In the Ischementioning

confidence: 97%

Protein Tyrosine Phosphorylation in the Ischemic Brain

2014

J Pharmacol Sci

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“…In this sense, it is interesting that transient global ischemia induced a rapid and sustained increase in the tyrosine phosphorylation of NR2 subunits in the hippocampus. 18,29) In addition to the possible effects of mGluR5-mediated increases in tyrosine phosphorylation of NR2A and NR2B on NMDA receptor ion channel properties, tyrosine phosphorylation may also modulate calpain-mediated truncation of receptor subunits. Src-mediated tyrosine phosphorylation significantly reduced calpain-induced truncation of NR2A and NR2B.…”

Section: Discussionmentioning

confidence: 99%

“…30) It has also been shown that tyrosine phosphorylated NR2B, but not NR2A, can bind to the SH2 domain of PI3-kinase. 29,31) In transfected HEK293 cells, the tyrosine dephosphorylation of Tyr-842 in NR2A induced downregulation of recombinant NR1/NR2A receptor. 32) Therefore, it is conceivable that a sustained increase in the tyrosine phosphorylation of NR2A subunit could not induce a sufficient downregulation of the NMDA receptor, although tyrosine phosphorylation sites in NR2A and NR2B mediated by mGluR5 in hippocampal neurons remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Metabotropic Glutamate Receptor 5 Activation Enhances Tyrosine Phosphorylation of the <i>N</i>-methyl-<small>D</small>-aspartate (NMDA) Receptor and NMDA-Induced Cell Death in Hippocampal Cultured Neurons

Biological & Pharmaceutical Bulletin

Besshoh

Marunouchi

et al. 2012

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The activation of group I metabotropic glutamate receptors (mGluRs), which are coupled with Gq-protein, initiates a variety physiological responses in different types of cells. While Gq-protein-coupled receptors can upregulate N-methyl-D-aspartate (NMDA) receptor function, group I mGluR-mediated regulations of NMDA receptor function are not fully understood. To determine biochemical roles of group I mGluRs in the regulation of the NMDA receptor, we have investigated changes in tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B induced by a selective mGluR5 agonist, (RS)-chloro-5-hydroxyphenylglycine (CHPG) in hippocampal neuronal cultures. Activation of mGluR5 by CHPG increased active-forms of Src. CHPG also enhanced tyrosine phosphorylation of NR2A and NR2B in hippocampal neuronal cultures. In addition, NMDA-induced cell death was enhanced by CHPG-induced mGluR5 stimulation at the concentration, which increased tyrosine phosphorylation of Src and NR2A/2B but did not induce cell death. This effect was inhibited by selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). The results suggest that in hippocampal neurons, mGluR5 may regulate NMDA receptor activity, involving tyrosine phosphorylation of NR2A and NR2B and may be involved in NMDA receptor-mediated cell injury. Key words N-methyl-D-aspartate receptor; metabotropic glutamate receptor; cell injuryAccumulating evidence indicates that metabotropic glutamate receptors (mGluRs) play a pivotal role in the regulation of numerous physiological responses to neurotransmitter glutamate in the central nervous system. mGluRs are a family of G-protein-coupled receptors and are composed of eight heterogeneous subtypes, which have been divided into three groups (I, II, and III) based on sequence homology, intracellular signal transduction mechanisms, and pharmacological profiles.1-3) Two types, mGluR1 and mGluR5, of group I mGluRs preferentially couple via Gq protein to activate phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate diacylglycerol and inositol 1,4,5-trisphosphate (IP 3 ). Group II and III mGluRs are coupled negatively via Gi protein to adenylyl cyclase second messenger system. It has been implicated that a stimulation of Gq-coupled receptors can activate Src family tyrosine kinases. 4,5) Because tyrosine phosphorylation potentiates functions of the N-methyl-D-aspartate (NMDA) receptor, which contributes to synaptic plasticity in the central nervous system, Gq-proteincoupled receptors can be involved in regulating NMDA receptor function. Indeed, a stimulation of Gq-coupled muscarinic and lysophosphatidic acid receptors can activate the NMDA receptor through protein tyrosine kinase Src. 6) Furthermore, evidences indicate that an activation of Gq-coupled mGluR5 also enhances NMDA current in hippocampal and subthalamic nucleus cells, [7][8][9] whereas an activation of mGluR1, but not mGluR5, induces a potentiation of the NMDA receptormediated current in cortical neurons.10) Although the contribu...

“…The experimental protocol was approved by the Committee of Animal Care and Use of Tokyo University of Pharmacy and Life Science. Transient (15 mins) forebrain ischemia was produced by the four-vessel occlusion procedure for rats described previously (Takagi et al, 2003). In brief, rats were anesthetized intraperitoneally with 40 mg/kg sodium pentobarbital.…”

Section: Animal Modelmentioning

confidence: 99%

Prevention of Apoptosis-Inducing Factor Translocation is a Possible Mechanism for Protective Effects of Hepatocyte Growth Factor against Neuronal Cell Death in the Hippocampus after Transient Forebrain Ischemia

Niimura

J Cereb Blood Flow Metab

et al. 2006

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Hepatocyte growth factor (HGF) is one of the prospective agents for therapy against a variety of neurologic and neurodegenerative disorders, although the precise mechanisms for the effect of HGF remain to be elucidated. We showed that treatment with HGF protected hippocampal cornu ammonis (CA) subregion 1 neurons from apoptotic cell death after transient forebrain ischemia. Accumulating evidence indicates that ischemia-induced neuronal damage occurs via caspase-independent pathways. In the present study, we focused on the localization of apoptosis-inducing factor (AIF), which is an important protein in the signal-transduction system through caspase-independent pathways, to investigate the possible mechanism for the protective effect of HGF after transient forebrain ischemia. Hepatocyte growth factor attenuated the increase in the expression of AIF protein in the nucleus after transient forebrain ischemia. We further explored the upstream components of AIF translocation. Primary DNA damage induced by Ca 2 + influx and subsequent NO formation are thought to be the initial events for AIF translocation, which results in the subsequent DNA damage by AIF. Hepatocyte growth factor prevented the primary oxidative DNA damage, as was estimated by using anti-8-OHdG (8-hydroxy-2 0 -deoxyguanosine) antibody. Oxidative DNA damage after ischemia is known to lead to the activation of poly(ADP-ribose) polymerase (PARP) and p53, resulting in AIF translocation. Marked increases in the PAR polymer formation and the expression of p53 protein after ischemia were effectively prevented by HGF treatment. In the present study, we first showed that HGF was capable of preventing neuronal cell death by inhibiting the primary oxidative DNA damage and then preventing the activation of the PARP/p53/AIF pathway.