The DOI matches its Crossref record; 52 of the 54 references it cites were found in a registry or an index.
DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke
Open accessAbstract
N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extrasynaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2B(CT)). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2B(CT) that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca(2+) influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extrasynaptic sites and this interaction acts as a central mediator for stroke damage.
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“Phosphorylation of S1303 in heterologous cells enhances NMDAR current (127, 128)”
From Synaptic memory and CaMKII (2023) · cites this paper as [128]
In the citing paper
“DAPK1 (FC = 1.08, p = 0.05) is a calcium-dependent serine/threonine kinase that is highly expressed in the cortex in AD [167], after ischemic damage [154], and in physiological ageing where it has been suggested to play a role in the decay of learning and memory with age [51].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [154]
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Citations
Cites
The molecular basis of CaMKII function in synaptic and behavioural memory
Lisman, J., Schulman, H., & Cline, H. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn753 · Cited by 1,860 · cited 2×
“CaMK-II is one of the most abundant Ca/CaM-dependent enzymes in the central neurons and participates in synaptic plasticity (Lisman et al., 2002) as well as in the cellular events responsible for ischemic neuronal death (Waxham et al.”
Mechanisms, challenges and opportunities in stroke
Lo, E. H., Dalkara, T., & Moskowitz, M. A. (2003) · Nature reviews. Neuroscience · doi:10.1038/nrn1106 · Cited by 1,808 · cited 6×
“Ca overload triggers multiple intracellular catabolic processes, and thus induces an irreversible death of neuronal cells in the brain (for review, see Lipton, 2006; Lo et al., 2003).”
InfluentialExtrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
Hardingham, G. E., Fukunaga, Y., & Bading, H. (2002) · Nature Neuroscience · doi:10.1038/nn835 · Cited by 1,686 · cited 3×
“DISCUSSION NMDA receptor NR2B subunits have recently become the major focus of studies in the treatment of stroke because of their unique features (Hardingham et al., 2002; Simpkins et al., 2003; Liu et al., 2007 ).”
Blockade of N -Methyl-D-Aspartate Receptors May Protect Against Ischemic Damage in the Brain
Simon, R. P., Swan, J. H., Griffiths, T., & Meldrum, B. S. (1984) · Science · doi:10.1126/science.6093256 · Cited by 1,682 · cited 3×
“These three groups of neurons were examined because they are known to be vulnerable to transient global ischemic insult (Simon et al., 1984; Pellegrini-Giampietro et al., 1997; Wang et al., 2003a; Liu et al., 2004; Peng et al., 2006).”
BackgroundCa 2+ -Induced Apoptosis Through Calcineurin Dephosphorylation of BAD
Wang, H., Pathan, N., Ethell, I. M., Krajewski, S., Yamaguchi, Y., Shibasaki, F., McKeon, F., Bobo, T., Franke, T. F., & Reed, J. C. (1999) · Science · doi:10.1126/science.284.5412.339 · Cited by 1,132
Glutamate release in severe brain ischaemia is mainly by reversed uptake
Rossi, D. J., Oshima, T., & Attwell, D. (2000) · Nature · doi:10.1038/35002090 · Cited by 1,128 · cited 4×
“This feature enables the receptor to detect extrasynaptic glutamate spillover in the brain during ischemic insults (Drejer et al., 1985; Rossi et al., 2000 ).”
BackgroundInfluentialXiong, Z., Zhu, X., Chu, X., Minami, M., Hey, J. G., Wei, W., MacDonald, J. F., Wemmie, J. A., Price, M. P., Welsh, M. J., et al. (2004) · Cell · doi:10.1016/j.cell.2004.08.026 · Cited by 1,037
Treatment of Ischemic Brain Damage by Perturbing NMDA Receptor- PSD-95 Protein Interactions
Aarts, M. M., Liu, Y., Liu, L., Besshoh, S., Arundine, M., Gurd, J. W., Wang, Y.-T., Salter, M. W., & Tymianski, M. (2002) · Science · doi:10.1126/science.1072873 · Cited by 998 · cited 2×
“Alternatively, recent studies have focused on NMDA receptor NR2B subunit downstream cell death signaling via interaction with PSD-95 (Aarts et al., 2002).”
Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond
Lipton, S. A. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1958 · Cited by 909 · cited 4×
“Ca 2+ overload triggers multiple intracellular catabolic processes, and thus induces an irreversible death of neuronal cells in the brain (for review, see Lipton, 2006; Lo et al., 2003).”
InfluentialS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration
Uehara, T., Nakamura, T., Yao, D., Shi, Z., Gu, Z., Ma, Y., Masliah, E., Nomura, Y., & Lipton, S. A. (2006) · Nature · doi:10.1038/nature04782 · Cited by 905 · cited 2×
“Ca 2+ overload triggers several downstream lethal reactions including nitrosative stress (Aarts et al., 2003; Uehara et al., 2006), oxidative stress (Kinouchi et al., 1991) and mitochondrial dysfunction (Krajewski et al., 1999; Fiskum et al., 1999).”
Cited by
Sorted by citations
Glutamate Receptor Ion Channels: Structure, Regulation, and Function
Traynelis, S. F., Wollmuth, L. P., McBain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., Hansen, K. B., Yuan, H., Myers, S. J., & Dingledine, R. (2010) · Pharmacological Reviews · doi:10.1124/pr.109.002451 · Cited by 3,568
“In particular, deleterious effects can be mediated by extrasynaptic receptors containing GluN2B subunits (Tu et al., 2010).”
BackgroundNMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
Paoletti, P., Bellone, C., & Zhou, Q. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3504 · Cited by 2,523
The Science of Stroke: Mechanisms in Search of Treatments
Moskowitz, M. A., Lo, E. H., & Iadecola, C. (2010) · Neuron · doi:10.1016/j.neuron.2010.07.002 · Cited by 1,930
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Hardingham, G. E., & Bading, H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2911 · Cited by 1,644
“A recent study has demonstrated that extrasynaptic NMDAR activity may be selectively enhanced in ischaemia through an intracellular signalling cascad”
Excitotoxicity and stroke: Identifying novel targets for neuroprotection
Lai, T. W., Zhang, S., & Wang, Y. T. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.11.006 · Cited by 1,106
“excitotoxic neuronal death following ischemia in vitro and in vivo, without affecting NMDAR channel activity or other downstream signaling proteins (Aarts et al., 2002; Sattler et al., 1999; Tu et al., 2010; Wang et al., 2003).”
Influential
Metadata
- Authors
- Tu, W., Xu, X., Peng, L., Zhong, X., Zhang, W., Soundarapandian, M. M., Belal, C., Wang, M., Jia, N., Zhang, W., Lew, F., Chan, S. L., Chen, Y., & Lu, Y.
- Affiliations
- University of Central Florida (US)
- Louisiana State University (US)
- Wright State University (US)
- Corresponding author
- Lu, Youming
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 140
- Issue
- 2
- Pages
- 222-234
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2820131
- OpenAlex
- W2112215250
- Cited by
- 493
- References
- 54
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 24 · 2023: 37 · 2022: 28 · 2021: 38 · 2020: 35 · 2019: 24 · 2018: 35 · 2017: 45 · 2016: 35 · 2015: 20 · 2014: 35 · 2013: 34 · 2012: 21
- FWCI
- 12.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
- Journal of International Crisis and Risk Communication Research (submittedVersion)
- Funders
- National Institute on Aging (R01AG033282YL, R01AG033282)
- National Institute of Neurological Disorders and Stroke (R01NS5051383YL, R01NS051383)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Keywords
- DAPK1, NMDA receptor, NR2B subunit, cerebral ischemia, stroke, extrasynaptic NMDA receptors, neuronal cell death, calcium influx, protein phosphorylation, neuroprotection
- MeSH terms
- Animals, Brain, Brain Ischemia, Neurons, Peptides, Recombinant Proteins, Receptors, N-Methyl-D-Aspartate, Cell Death, Calcium-Calmodulin-Dependent Protein Kinases, Stroke, Apoptosis Regulatory Proteins, Mice, tat Gene Products, Human Immunodeficiency Virus, Death-Associated Protein Kinases
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