Activation of NR2A Receptors Induces Ischemic Tolerance through CREB Signaling

Terasaki, Yasukazu; Sasaki, Tsutomu; Yagita, Yoshiki; Okazaki, Shuhei; Sugiyama, Yukio; Oyama, Naoki; Omura-Matsuoka, Emi; Sakoda, Saburo; Kitagawa, Kazuo

doi:10.1038/jcbfm.2010.18

Cited by 82 publications

(58 citation statements)

References 42 publications

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“…We demonstrate for the first time that the upregulation of TDP-43 is mediated by the activation of NR2AR after glutamate accumulation. Recent evidence shows that NR2AR activation promotes neuronal survival in acute CNS injury such as cerebral ischemia and traumatic spinal injury (Alilain and Goshgarian, 2008;Liu et al, 2007;Terasaki et al, 2010). However, the underlying mechanisms remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Liao

Cui

et al. 2012

Journal of Cell Science

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SummaryThe dysfunction of TAR DNA-binding protein-43 (TDP-43) is implicated in neurodegenerative diseases. However, the function of TDP-43 is not fully elucidated. Here we show that the protein level of endogenous TDP-43 in the nucleus is increased in mouse cortical neurons in the early stages, but return to basal level in the later stages after glutamate accumulation-induced injury. The elevation of TDP-43 results from a downregulation of phosphatase and tensin homolog (PTEN). We further demonstrate that activation of NR2A-containing NMDA receptors (NR2ARs) leads to PTEN downregulation and subsequent reduction of PTEN import from the cytoplasm to the nucleus after glutamate accumulation. The decrease of PTEN in the nucleus contributes to its reduced association with TDP-43, and thereby mediates the elevation of nuclear TDP-43. We provide evidence that the elevation of nuclear TDP-43, mediated by NR2AR activation and PTEN downregulation, confers protection against cortical neuronal death in the late stages after glutamate accumulation. Thus, this study reveals a NR2AR-PTEN-TDP-43 signaling pathway by which nuclear TDP-43 promotes neuronal survival. These results suggest that upregulation of nuclear TDP-43 represents a self-protection mechanism to delay neurodegeneration in the early stages after glutamate accumulation and that prolonging the upregulation process of nuclear TDP-43 might have therapeutic significance.

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Section: Discussionmentioning

confidence: 99%

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Liao

Cui

et al. 2012

Journal of Cell Science

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“…It is noteworthy that several studies have indicated that NMDA receptor subtypes differ in their ability to cause cell death. GluN2B-containing NMDA receptors initiate cell death, whereas GluN2A-containing receptors have been reported to contribute to neuroprotection signaling in traumatic mechanical injury and ischemia models ( jpet.aspetjournals.org Terasaki et al, 2010). This may correspond to an enrichment of GluN2A and GluN2B subunits in synaptic and extrasynaptic compartments, respectively (Tovar and Westbrook, 1999;Lozovaya et al, 2004), and the ability of synaptic NMDA receptors to promote neuroprotection, whereas extrasynaptic NMDA receptor activation signals to neuronal cell death (Hardingham and Bading, 2003;Papadia et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…One intriguing possibility is that the potentiation of synaptic NMDA receptors containing the GluN2A subunit may stimulate neuroprotective-signaling pathways Terasaki et al, 2010). In an in vivo context, direct agonist activation would activate inappropriate receptors, whereas a potentiator should specifically increase the response of endogenously activated receptors, thus enhancing an appropriate biological response.…”

Section: Discussionmentioning

confidence: 99%

A Novel Family of Negative and Positive Allosteric Modulators of NMDA Receptors

Costa¹,

Irvine²,

Fang³

et al. 2010

J Pharmacol Exp Ther

173

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The N-methyl-D-aspartate (NMDA) receptor family regulates various central nervous system functions, such as synaptic plasticity. However, hypo-or hyperactivation of NMDA receptors is critically involved in many neurological and psychiatric conditions, such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Consequently, subtype-selective positive and negative modulators of NMDA receptor function have many potential therapeutic applications not addressed by currently available compounds. We have identified allosteric modulators with several novel patterns of NMDA receptor subtype selectivity that have a novel mechanism of action. In a series of carboxylated naphthalene and phenanthrene derivatives, compounds were identified that selectively potentiate responses at GluN1/GluN2A [e.g., 9-iodophenanthrene-3-carboxylic acid (UBP512)]; GluN1/GluN2A and GluN1/GluN2B [9-cyclopropylphenanthrene-3-carboxylic acid (UBP710)]; GluN1/GluN2D [3,5-dihydroxynaphthalene-2-carboxylic acid (UBP551)]; or GluN1/GluN2C and GluN1/GluN2D receptors [6-, 7-, 8-, and 9-nitro isomers of naphth[1,2-c][1,2,5]oxadiazole-5-sulfonic acid (NSC339614)] and have no effect or inhibit responses at the other NMDA receptors. Selective inhibition was also observed; UBP512 inhibits only GluN1/GluN2C and GluN1/GluN2D receptors, whereas 6-bromo-2-oxo-2H-chromene-3-carboxylic acid (UBP608) inhibits GluN1/ GluN2A receptors with a 23-fold selectivity compared with GluN1/ GluN2D receptors. The actions of these compounds were not competitive with the agonists L-glutamate or glycine and were not voltage-dependent. Whereas the N-terminal regulatory domain was not necessary for activity of either potentiators or inhibitors, segment 2 of the agonist ligand-binding domain was important for potentiating activity, whereas subtype-specific inhibitory activity was dependent upon segment 1. In terms of chemical structure, activity profile, and mechanism of action, these modulators represent a new class of pharmacological agents for the study of NMDA receptor subtype function and provide novel lead compounds for a variety of neurological disorders.

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“…MCAO in male mice led to a spike in pAMPK levels 4 h after IPC and reduction after 72 h, suggesting that downregulation of AMPK contributes toward delayed PC [91]. Finally, the roles of many key players like HIF-2α, SIRT1, and CREB suspected of being part of the preconditioning cascade are now established [85,92,93].…”

Section: Enzymes and Receptorsmentioning

confidence: 92%

Cerebral Ischemic Preconditioning: the Road So Far…

Sangwan

Sharma

et al. 2015

Mol Neurobiol

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Cerebral preconditioning constitutes the brain's adaptation to lethal ischemia when first exposed to mild doses of a subtoxic stressor. The phenomenon of preconditioning has been largely studied in the heart, and data from in vivo and in vitro models from past 2-3 decades have provided sufficient evidence that similar machinery exists in the brain as well. Since preconditioning results in a transient protective phenotype labeled as ischemic tolerance, it can open many doors in the medical warfare against stroke, a debilitating cerebrovascular disorder that kills or cripples thousands of people worldwide every year. Preconditioning can be induced by a variety of stimuli from hypoxia to pharmacological anesthetics, and each, in turn, induces tolerance by activating a multitude of proteins, enzymes, receptors, transcription factors, and other biomolecules eventually leading to genomic reprogramming. The intracellular signaling pathways and molecular cascades behind preconditioning are extensively being investigated, and several first-rate papers have come out in the last few years centered on the topic of cerebral ischemic tolerance. However, translating the experimental knowledge into the clinical scaffold still evades practicality and faces several challenges. Of the various preconditioning strategies, remote ischemic preconditioning and pharmacological preconditioning appears to be more clinically relevant for the management of ischemic stroke. In this review, we discuss current developments in the field of cerebral preconditioning and then examine the potential of various preconditioning agents to confer neuroprotection in the brain.

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Activation of NR2A Receptors Induces Ischemic Tolerance through CREB Signaling

Cited by 82 publications

References 42 publications

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

A Novel Family of Negative and Positive Allosteric Modulators of NMDA Receptors

Cerebral Ischemic Preconditioning: the Road So Far…

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