NMDA receptor activation results in tyrosine phosphorylation of NMDA receptor subunit 2A(NR2A) and interaction of Pyk2 and Src with NR2A after transient cerebral ischemia and reperfusion

Liu, Yong; Zhang, Guangyi; Gao, Can; Hou, Xiaoyu

doi:10.1016/s0006-8993(01)02619-1

Cited by 78 publications

(54 citation statements)

References 25 publications

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“…Src family kinases are activated rapidly, leading to up-regulation of NMDAR function [15] . Our previous study has shown that NR2A tyrosine phosphorylation induced by transient ischemia and reperfusion exhibits a rapid and sustained rise, a process mediated by PSD-95 [19] that also correlates with Src [24] . In this study, we examined the alteration of NR2A tyrosine phosphorylation and the as- PSD-95 binds to postsynaptic NMDARs, causing receptor clustering to the plasma membrane and creating a scaffold for numerous downstream signaling cascades [25,26] , and regulating NMDA channel gating [27] .…”

Section: Discussionmentioning

confidence: 95%

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Knock-down of postsynaptic density protein 95 expression by antisense oligonucleotides protects against apoptosis-like cell death induced by oxygen-glucose deprivation in vitro

et al. 2012

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Section: Discussionmentioning

confidence: 95%

“…The Src family is critical for regulating the tyrosine phosphorylation of NMDARs and the opening of NMDAR ion channels [5,19,24] .…”

Section: Discussionmentioning

confidence: 99%

Knock-down of postsynaptic density protein 95 expression by antisense oligonucleotides protects against apoptosis-like cell death induced by oxygen-glucose deprivation in vitro

et al. 2012

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“…NMDA receptor activation increases Ca 2+ influx and activates Ca 2+ -dependent Pyk2 (33) and its substrate Src (33,34), which in turn phosphorylates GluK2 and up-regulates kainate receptor function. The tyrosine phosphorylation-induced opening of GluK2-containing channels may be due to a conformational change.…”

Section: Discussionmentioning

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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“…PYK2 regulation by calcineurin Menegon et al, 1999). Although it is likely that PYK2 plays an important role in post-synaptic densities, because of its interaction with NMDA receptors and associated scaffold proteins (Bongiorno-Borbone et al, 2005;Cheung et al, 2000;Heidinger et al, 2002;Liu et al, 2001;Seabold et al, 2003), it does not appear to be enriched in spines. By contrast, deleted or mutated forms of PYK2 accumulate in the nucleus of transfected COS-7 cells (Aoto et al, 2002) and PYK2 is localized in the nucleus in chondrocytes and keratinocytes (Arcucci et al, 2006;Schindler et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin is essential for depolarization-induced nuclear translocation and tyrosine phosphorylation of PYK2 in neurons

Faure

Corvol

Toutant

et al. 2007

Journal of Cell Science

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Proline-rich tyrosine kinase 2 (PYK2) is a non-receptor tyrosine kinase expressed in many cell types and enriched in neurons. PYK2 is a cytoplasmic enzyme activated by increases in cytosolic free Ca2+ through an unknown mechanism. We report that depolarization or electrical stimulation of hippocampal slices induced a rapid and transient nuclear accumulation of PYK2. Depolarization of cultured neurons or PC12 cells also triggered a Ca2+-dependent nuclear accumulation of PYK2, much more pronounced than that induced by blockade of nuclear export with leptomycin B. Src-family kinase activity, PYK2 autophosphorylation and kinase activity were not required for its nuclear translocation. Depolarization induced a slight decrease in PYK2 apparent molecular mass, compatible with a Ca2+-activated dephosphorylation. Pretreatment of PC12 cells with inhibitors of calcineurin (protein phosphatase 2B), cyclosporin A and FK506, prevented depolarization-induced nuclear translocation and tyrosine phosphorylation of PYK2. Transfection with dominant-negative and constitutively active calcineurin-A confirmed the role of calcineurin in the regulation of PYK2 tyrosine phosphorylation and nuclear accumulation. Our results show that depolarization independently induces nuclear translocation and tyrosine phosphorylation of PYK2, and that both responses require calcineurin activation. We suggest that PYK2 exerts some of its actions in the nucleus and that the effects of calcineurin inhibitors may involve PYK2 inhibition.

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NMDA receptor activation results in tyrosine phosphorylation of NMDA receptor subunit 2A(NR2A) and interaction of Pyk2 and Src with NR2A after transient cerebral ischemia and reperfusion

Cited by 78 publications

References 25 publications

Knock-down of postsynaptic density protein 95 expression by antisense oligonucleotides protects against apoptosis-like cell death induced by oxygen-glucose deprivation in vitro

Knock-down of postsynaptic density protein 95 expression by antisense oligonucleotides protects against apoptosis-like cell death induced by oxygen-glucose deprivation in vitro

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

Calcineurin is essential for depolarization-induced nuclear translocation and tyrosine phosphorylation of PYK2 in neurons

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