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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]
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“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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“…reasoned that, in comparison with the TAT-GluN2B (without CTM) that reduces NMDAR-mediated excitotoxicity by disrupting the DAPK1-NMDAR interaction 26 , our targeting peptide TAT-GluN2BCTM, by knocking down DAPK1, may protect neurons against not only NMDAR-mediated excitotoxicity, but also other…”
InfluentialDeath Associated Protein Kinase 1 (DAPK1): A Regulator of Apoptosis and Autophagy
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“In a recent study, DAPK1 is identified as a new component of the neuronal death signaling complex (NDC; Lai et al., 2011), which act as a signaling amplifier of N-methyl-D-aspartate (NMDA) receptors at extrasynaptic sites for mediating brain damage in stroke (Tu et al., 2010).”
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“The shRNA sequences were designed based on the GPR30 (Hsieh et al., 2007) and DAPK1 (Tu et al., 2010) sequences as reported previously.”
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“One promising candidate is the death-associated protein kinase 1 (DAPK1) that associates with NR2B in ischemic conditions, thereby potentiating NMDA receptor activity at extrasynaptic sites (Tu et al., 2010).”
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“However, the function of NMDARs, especially GluN2B-containing NMDARs, has been reported to be enhanced in an animal model of cerebral ischemia, mainly through increased phosphorylation of GluN2B at Ser(1303) (27).”
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“Notably, in cerebral neurons, calcium-activated calcineurin was identified as the phosphatase that dephosphorylates Ser308 in response to ischemic insults [22].”
BackgroundThe NMDA receptor complex: a multifunctional machine at the glutamatergic synapse
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“Moreover, GluN2B-NMDARs are associated with pro-death cellular pathways [51, 52].”
BackgroundDeath‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes
Farag, A. K., & Roh, E. J. (2018) · Medicinal Research Reviews · doi:10.1002/med.21518 · Cited by 119
The Role of Excitotoxic Programmed Necrosis in Acute Brain Injury
Fujikawa, D. G. (2015) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2015.03.004 · Cited by 114
Perinatal brain damage: The term infant
Hagberg, H., Edwards, A. D., & Groenendaal, F. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.09.011 · Cited by 115
Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity
Frasca, A., Aalbers, M. W., Frigerio, F., Fiordaliso, F., Salio, M., Gobbi, M., Cagnotto, A., Gardoni, F., Battaglia, G. S., Hoogland, G., et al. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.04.024 · Cited by 104
Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects
Li, S.-X., Han, Y., Xu, L., Yuan, K., Zhang, R.-X., Sun, C.-Y., Xu, D.-F., Yuan, M., Deng, J.-H., Meng, S.-Q., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.85 · Cited by 100
Verma, M., Wills, Z. P., & Chu, C. T. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00523 · Cited by 103
“…phospholipases, and endonucleases, engagement of extrasynaptic NMDARs shuts off CREB signaling (Hardingham et al., 2002), while activating death associated protein kinase 1 (DAPK1) and neuronal nitric oxide synthase (nNOS) bound to the NR2B cytosolic tail (Tu et al., 2010; Martel et al., 2012).”
Kim, B. M., You, M.-H., Chen, C.-H., Lee, S., Hong, Y., Hong, Y., Kimchi, A., Zhou, X. Z., & Lee, T. H. (2014) · Cell Death & Disease · doi:10.1038/cddis.2014.216 · Cited by 98
Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity
Vidaurre, Ó. G., Gascón, S., Deogracias, R., Sobrado, M., Cuadrado, E., Montaner, J., Rodríguez‐Peña, A., & Díaz‐Guerra, M. (2012) · Cell Death and Disease · doi:10.1038/cddis.2011.143 · Cited by 100
“consistent with the coupling of GluN2B subunits of the extrasynaptic NMDARs to excitotoxic pathways.(2,29) Also supporting the importance of the source of calcium, the”
BackgroundMira, R. G., & Cerpa, W. F. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00924-0 · Cited by 98
NMDARs in Cell Survival and Death: Implications in Stroke Pathogenesis and Treatment
Ge, Y., Chen, W., Axerio-Cilies, P., & Wang, Y. T. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.03.001 · Cited by 97
IQGAP1 regulates NR2A signaling, spine density, and cognitive processes
Gao, C., Frausto, S. F., Guedea, A. L., Tronson, N. C., Jovasevic, V., Leaderbrand, K., Corcoran, K. A., Guzman, Y. F., Swanson, G. T., & Radulovic, J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1300-11.2011 · Cited by 85
“Alternatively, preferential NR2B scaffolds, such as SynGAP1 (Kim et al., 2005), RACK1 (Yaka et al., 2003), SAP102 (Petralia et al., 2005), or DAPK1 (Tu et al., 2010), might have compensated for the loss of IQGAP1.”
BackgroundFrega, M., Pasquale, V., Tedesco, M., Marcoli, M., Contestabile, A., Nanni, M., Bonzano, L., Maura, G., & Chiappalone, M. (2011) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2011.08.001 · Cited by 93
MicroRNA-9 Mediates the Cell Apoptosis by Targeting Bcl2l11 in Ischemic Stroke
Wei, N., Xiao, L., Xue, R., Zhang, D., Zhou, J., Ren, H., Guo, S., & Xu, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9605-4 · Cited by 93
“Neurological scores was assayed daily using modified 7-point neurological scales [18]: 0, no observable neurological deficits; 1, flexion of the contralateral torso; 2, circling to the ipsilateral side but normal posture at rest; 3, circling to the ipsilateral side; 4, rolling to the ipsilateral side; 5, leaning to th…”
MethodWei, R., Zhang, L., Hu, W., Wu, J., & Zhang, W. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.01.009 · Cited by 93
“With bioinformatics, we identified shared putative miR-26a-5p binding sites in AK038897 as well as in the 3′-UTR of DAPK1, a central mediator of ischemic neuronal death (Shamloo et al., 2005; Tu et al., 2010).”
Self-citationFan, J., Gladding, C. M., Wang, L., Zhang, L. Y. J., Kaufman, A. M., Milnerwood, A. J., & Raymond, L. A. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.019 · Cited by 94
Poly-Arginine and Arginine-Rich Peptides are Neuroprotective in Stroke Models
Meloni, B. P., Brookes, L. M., Clark, V. W., Cross, J. L., Edwards, A. B., Anderton, R. S., Hopkins, R. M., Hoffmann, K., & Knuckey, N. W. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.11 · Cited by 91
Benarroch, E. E. (2011) · Neurology · doi:10.1212/wnl.0b013e31821b7cc9 · Cited by 90
Critical Role of Increased PTEN Nuclear Translocation in Excitotoxic and Ischemic Neuronal Injuries
Zhang, S., Taghibiglou, C., Girling, K., Dong, Z., Lin, S., Lee, W., Shyu, W., & Wang, Y. T. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5661-12.2013 · Cited by 91
“1D) (Liu et al., 2007; Okamoto et al., 2009; Tu et al., 2010; Lai et al., 2011).”
DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific
Goodell, D. J., Zaegel, V., Coultrap, S. J., Hell, J. W., & Bayer, K. U. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.068 · Cited by 88
“…this LTD signaling pathway is unlikely, as the pharmacogenetic approach used here indicates that DAPK1 blockade of CaMKII/GluN2B binding is the essential function of DAPK1 in LTD. DAPK1 binding to GluN2B has also been prominently implicated in the pathological functions of DAPK1 (Tu et al., 2010).”
BackgroundMethodInfluentialKim, N., Chen, D., Zhou, X. Z., & Lee, T. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133131 · Cited by 89
“However, the genetic deletion of DAPK1 in vivo or in vitro protects neurons by blocking the interaction between DAPK1 and GluN2B-containing NMDA receptors [93].”
BackgroundInfluentialMeloni, B. P., Milani, D., Edwards, A. B., Anderton, R. S., Doig, R. O., Fitzgerald, M., Palmer, T. N., & Knuckey, N. W. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.06.002 · Cited by 90
Genomic and epigenetic profiles of gastric cancer: Potential diagnostic and therapeutic applications
Yamashita, K., Sakuramoto, S., & Watanabe, M. (2010) · Surgery Today · doi:10.1007/s00595-010-4370-5 · Cited by 86
“recently found that DAPK, which is a well-known methylated tumor suppressor gene, was responsible for ischemia-induced neuronal cell death in mice, where DAPK coprecipitated with the NMDA receptor complex and interacted directly with the NMDAR2B subunit.(177) Ischemia subsequently activated DAPK, and activated DAPK se…”
BackgroundDiscovery and development of NA-1 for the treatment of acute ischemic stroke
Ballarin, B., & Tymianski, M. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2018.5 · Cited by 86
Meloni, B. P., Mastaglia, F. L., & Knuckey, N. W. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00108 · Cited by 85
Li, X., Chen, W., Pan, K., Li, H., Pang, P., Guo, Y., Shu, S., Cai, Y., Pei, L., Liu, D., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0207-0 · Cited by 85
Self-citationPaul, S., & Connor, J. A. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06835.x · Cited by 85
“Few studies have also addressed the role of NR2A and NR2B receptor subtypes in glutamate-mediated excitotoxicity in vivo (Morikawa et al. 1998; Liu et al. 2007; Tu et al. 2010).”
BackgroundResultDAPK1 Signaling Pathways in Stroke: from Mechanisms to Therapies
Wang, S., Shi, X.-D., Li, H., Pang, P., Pei, L., Shen, H., & Lu, Y. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0008-y · Cited by 83
“reported that DAPK1 is directly linked to the NR2B subunit and initiates a specific cell death signaling [18].”
Self-citationDAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity
Wu, P.-R., Tsai, P.-I., Chen, G., Chou, H.-J., Huang, Y.-P., Chen, Y. H., Lin, M.-Y., Kimchi, A., Chien, C.-T., & Chen, R.-H. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.2 · Cited by 82
Self-citationYokoyama, T., Kosaka, Y., & Mizuguchi, M. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00893 · Cited by 84
The Emergence of NMDA Receptor Metabotropic Function: Insights from Imaging
Doré, K., Aow, J., & Malinow, R. (2016) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2016.00020 · Cited by 83
Wang, J., Liu, F., Yang, F., Wang, Y., Qi, X., Li, Y., Hu, Q., Zhu, M. X., & Xu, T. (2020) · Nature Communications · doi:10.1038/s41467-019-13873-0 · Cited by 81
DeGregorio‐Rocasolano, N., Martı́, O., Ponce, J., Castelló‐Ruiz, M., Millán, M., Guirao, V., García‐Yébenes, I., Salom, J. B., Ramos‐Cabrer, P., Alborch, E., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.11.026 · Cited by 80
“The following primary antibodies were used for immunocytochemistry or WB: rabbit anti-rat Tf polyclonal antibody (4 µg/ ml, Cappel 55720), mouse anti-hTf monoclonal antibodies OT-1 and HTF-14 (5 µg/ml, Acris Antibodies BM2704 and BM745S, respectively), mouse anti-tubulin (0.25 µg/ml, Sigma-Aldrich T6074), rabbit antia…”
BackgroundInfluentialBhattacharya, S., Khatri, A., Swanger, S. A., DiRaddo, J. O., Yi, F., Hansen, K. B., Yuan, H., & Traynelis, S. F. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.010 · Cited by 77
“…approaches to express triheteromeric NMDARs of known subunit composition in heterologous systems is a principal reason for the deficit of experimentation on triheteromeric receptors (Javitt and Zukin, 1991; Paoletti and Neyton, 2007; Traynelis et al., 2010; Tu et al., 2010; VanDongen, 2008).”
BackgroundWang, P., Cui, Y., Liu, Y., Li, Z., Bai, H., Zhao, Y., & Chang, Y. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102475 · Cited by 77
“Oxygen-glucose deprivation-reoxygenation (OGD/R) is a widely accepted model for studying ischemic reperfusion in vitro [39,40].”
BackgroundModes of Neuronal Calcium Entry and Homeostasis following Cerebral Ischemia
Cross, J. L., Meloni, B. P., Bakker, A. J., Lee, S., & Knuckey, N. (2010) · Stroke Research and Treatment · doi:10.4061/2010/316862 · Cited by 77
“It has been demonstrated that following ischemia and NDMA receptor activation, NR2A and NR3 subunit containing receptors promote neuronal survival signalling pathways [14, 22, 23], while NR2B-containing receptors mediate neuronal death signals [24–28].”
Balu, D. T., Pantazopoulos, H., Huang, C. C., Muszynski, K., Harvey, T. L., Uno, Y., Rorabaugh, J. M., Galloway, C. R., Botz-Zapp, C. A., Berretta, S., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104511 · Cited by 78
Levin‐Salomon, V., Bialik, S., & Kimchi, A. (2013) · APOPTOSIS · doi:10.1007/s10495-013-0918-3 · Cited by 76
Insights into the neuropathology of cerebral ischemia and its mechanisms
Ahad, M. A., Kumaran, K. R., Tiang, N., Mansor, N. I., Effendy, M. A., Damodaran, T. K., Lingam, K., Wahab, H. A., Nordin, N., Liao, P. H., et al. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0099 · Cited by 77
Wang, J., Li, X., Song, Y., Su, Q., Xiaohalati, X., Yang, W., Xu, L., Cai, B., Wang, G., Wang, Z., et al. (2020) · Bioactive Materials · doi:10.1016/j.bioactmat.2020.12.017 · Cited by 74
“The C57BL/6J mice were subjected to transient focal cerebral ischemia by middle cerebral artery blockade (MCAO) with a suture as previously described [19].”
MethodA Novel Mechanism of Spine Damages in Stroke via DAPK1 and Tau
Pei, L., Wang, S., Jin, H., Bi, L., Wei, N., Yan, H., Yang, X., Yao, C., Xu, M., Shu, S., et al. (2015) · Cerebral Cortex · doi:10.1093/cercor/bhv096 · Cited by 74
“Stroke is caused by acute brain artery bursting or cerebral embolism, leading to neuronal death and sever dysfunction of synaptic transmission (Tu et al. 2010).”
InfluentialSelf-citation
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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