Phosphorylation and Assembly of Glutamate Receptors After Brain Ischemia

Zhang, Fan; Guo, Ailan; Liu, Chunli; Comb, Micheal; Hu, Bingren

doi:10.1161/strokeaha.112.667253

Cited by 36 publications

(38 citation statements)

References 31 publications

(55 reference statements)

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“…Besides, a previous study has also revealed that the association of Fyn with NMDARs is enhanced after global transient ischemia (45). By combining this evidence with our findings, we believed that the mechanism of regulating Tyr(P)-1472 via phosphorylated Tyr-1070 is probably also involved in neurological disorders such as ischemic injury (16,44). In future studies it will be interesting to explore whether manipulation of the Tyr-1070 phosphorylation state and/or the association of GluN2B with Fyn can be targets to ease the damage after ischemic insult.…”

Section: Discussionsupporting

confidence: 85%

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Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

Fang

et al. 2015

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 85%

“…Interestingly, we noted that recent studies have indicated that both Tyr(P)-1070 and Tyr(P)-1472 levels increase after global transient ischemia and reperfusion (16,44). Besides, a previous study has also revealed that the association of Fyn with NMDARs is enhanced after global transient ischemia (45).…”

Section: Discussionmentioning

confidence: 63%

Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

Fang

et al. 2015

Journal of Biological Chemistry

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“…Src kinase, a central tyrosine kinase at the excitatory postsynaptic density in the adult central nervous system, is significantly activated after brain ischemia (15)(16)(17)(18). Therefore, we investigated whether GluK2 subunits are phosphorylated by Src kinases during ischemia and reperfusion (I/R) in the vulnerable hippocampal CA1 subfield.…”

Section: Brain Ischemia and Reperfusion Increase Gluk2 Phosphorylatiomentioning

confidence: 99%

“…In particular, serine/threonine phosphorylation is important in the functional regulation of NMDA (5), AMPA (6), and kainate receptors (6)(7)(8)(9), with tyrosine phosphorylation of NMDA receptors the most extensively studied (10,11). There is accumulating evidence to show that tyrosine phosphorylation of NMDA receptors modulates their assembly at synapses after brain ischemia (12)(13)(14)(15). However, less is known about the regulation of kainate receptor activity by tyrosine phosphorylation.…”

mentioning

confidence: 99%

Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia

Zhu

Kong

et al. 2014

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

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Although kainate receptors play important roles in ischemic stroke, the molecular mechanisms underlying postischemic regulation of kainate receptors remain unclear. In this study we demonstrate that Src family kinases contribute to the potentiation of kainate receptor function. Brain ischemia and reperfusion induce rapid and sustained phosphorylation of the kainate receptor subunit GluK2 by Src in the rat hippocampus, implicating a critical role for Src-mediated GluK2 phosphorylation in ischemic brain injury. The NMDA and kainate receptors are involved in the tyrosine phosphorylation of GluK2. GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. In addition, GluK2 phosphorylation at Y590 facilitates the endocytosis of GluK2 subunits, and the activation of JNK3 and its substrate c-Jun after long-term kainate treatment. Thus, Src phosphorylation of GluK2 plays an important role in the opening of kainate receptor channels and downstream proapoptosis signaling after brain ischemia. The present study reveals an additional mechanism for the regulation of GluK2-containing kainate receptors by Src family kinases, which may be of pathological significance in ischemic stroke.K ainate receptors are widely expressed in the mammalian central nervous system, particularly in the hippocampus, where they are involved in synaptic transmission (1), neuronal plasticity (2), and excitotoxic lesions (3). Overactivation of postsynaptic kainate receptor-mediated responses is associated with neurological disorders resulting from ischemic stroke (4). However, the intracellular processes responsible for the postischemic up-regulation of kainate receptors, and its molecular consequences, have not yet been elucidated.Reversible phosphorylation is one of the most common mechanisms regulating the function of receptor proteins. In particular, serine/threonine phosphorylation is important in the functional regulation of NMDA (5), AMPA (6), and kainate receptors (6-9), with tyrosine phosphorylation of NMDA receptors the most extensively studied (10, 11). There is accumulating evidence to show that tyrosine phosphorylation of NMDA receptors modulates their assembly at synapses after brain ischemia (12-15). However, less is known about the regulation of kainate receptor activity by tyrosine phosphorylation. Src is an important member of Src family kinases, the largest family of nonreceptor protein tyrosine kinases, and is highly expressed in the brain. Brain ischemia increases Src kinase activity in vulnerable brain regions, including the hippocampus (15-18), but it is not known whether Src phosphorylates kainate receptors.Kainate receptors are tetrameric glutamate-gated ion channels consisting of GluK1-GluK5 subunits, formerly known as GluR5-GluR7, KA1, and KA2, respectively. Functional kainate receptors can be expressed as homo...

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“…Both GluN2A and GluN2B subunits of the NMDA receptor have been shown to be phosphorylated on their tyrosine residues (7,8). Furthermore, it was earlier demonstrated that NMDA receptor-mediated currents are potentiated by tyrosine phosphorylation (9).…”

Section: Tyrosine Phosphorylation Of Glutamate Receptors In the Ischementioning

confidence: 99%

Protein Tyrosine Phosphorylation in the Ischemic Brain

Takagi

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.

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Phosphorylation and Assembly of Glutamate Receptors After Brain Ischemia

Cited by 36 publications

References 31 publications

Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia

Protein Tyrosine Phosphorylation in the Ischemic Brain

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