Cited by 88Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsTreatment of Major Depression

DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific

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Goodell, Dayton J., Zaegel, Vincent, Coultrap, Steven J., Hell, Johannes W., Bayer, K. Ulrich·2017·Cell Reports

Abstract

The death-associated protein kinase 1 (DAPK1) is a potent mediator of neuronal cell death. Here, we find that DAPK1 also functions in synaptic plasticity by regulating the Ca 2+ /calmodulin (CaM)-dependent protein kinase II (CaMKII). CaMKII and T286 autophosphorylation are required for both long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory, and cognition. T286-autophosphorylation induces CaMKII binding to the NMDA receptor (NMDAR) subunit GluN2B, which mediates CaMKII synaptic accumulation during LTP. We find that the LTP specificity of CaMKII synaptic accumulation is due to its LTD-specific suppression by calcineurin (CaN)-dependent DAPK1 activation, which in turn blocks CaMKII binding to GluN2B. This suppression is enabled by competitive DAPK1 versus CaMKII binding to GluN2B. Negative regulation of DAPK1/GluN2B binding by Ca 2+ /CaM results in synaptic DAPK1 removal during LTP but retention during LTD. A pharmacogenetic approach showed that suppression of CaMKII/GluN2B binding is a DAPK1 function required for LTD.

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Crossref · 10.1016/j.celrep.2017.05.068

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  • DAPK1 plays a role in LTD, where its activation via calcineurin-dependent dephosphorylation leads to GluN2B phosphorylation at Ser-1303, strengthening DAPK1 interaction and preventing CaMKII binding.

    “DAPK1 also plays a role in LTD, where its activation via calcineurin-dependent dephosphorylation leads to GluN2B phosphorylation at Ser-1303, strengthening DAPK1 interaction and preventing CaMKII binding.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [54]

  • DAPK1 functions as a refined physiological regulator during LTD, where its recruitment to GluN2B prevents CaMKII accumulation in the spine, thereby enabling bidirectional control of synaptic strength.

    “Beyond its pathological role in excitotoxicity, DAPK1 functions as a refined physiological regulator during long-term depression (LTD), where its recruitment to GluN2B prevents CaMKII accumulation in the spine, thereby enabling bidirectional control of synaptic strength [48,54].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [54]

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Research works printed but not linked: 5

  1. Barcomb K Buard I Coultrap SJ Kulbe JR O’Leary H Benke TA Bayer KU 2014 Autonomous CaMKII requires further stimulation by Ca2+/calmodulin for enhancing synaptic strength The FASEB Journal 28 3810 3819 24843070 PMC4101658
  2. Malenka RC Bear MF 2004 LTP and LTD: an embarrassment of riches Neuron 44 5 21 15450156
  3. Marsden KC Shemesh A Bayer KU Carroll RC 2010 Selective translocation of Ca2+/calmodulin protein kinase IIalpha (CaMKIIalpha) to inhibitory synapses Proc. Natl. Acad. Sci. U.S.a 107 20559 20564 21059908 PMC2996683
  4. Shonesy BC Jalan-Sakrikar N Cavener VS Colbran RJ 2014 CaMKII: a molecular substrate for synaptic plasticity and memory Prog Mol Biol Transl Sci 122 61 87 24484698
  5. Squire LR Wixted JT 2011 The cognitive neuroscience of human memory since HM Annu. Rev. Neurosci 34 259 21456960 PMC3192650

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Authors
Goodell, D. J., Zaegel, V., Coultrap, S. J., Hell, J. W., & Bayer, K. U.
Affiliations
  • University of Colorado Anschutz (US)
  • University of California, Davis (US)
Corresponding author
Bayer, K. Ulrich
Venue
Cell Reports
Publisher
Elsevier BV
Published
2017-06
Volume
19
Issue
11
Pages
2231-2243
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2625709293
Cited by
88
References
67
Citations by year
2026: 8 · 2025: 12 · 2024: 9 · 2023: 11 · 2022: 12 · 2021: 13 · 2020: 11 · 2019: 4 · 2018: 7 · 2017: 1
FWCI
3.08
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
NIH (F31NS092265, R01MH097887, R01AG055357, R01NS081248, R01NS080851)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
DAPK1, CaMKII, GluN2B, NMDA receptor, long-term depression, long-term potentiation, synaptic plasticity, CaMKII autophosphorylation, calcineurin, Ca2+/calmodulin signaling, protein-protein binding
MeSH terms
Amino Acid Sequence, Animals, Humans, Memory, Neuronal Plasticity, Phosphorylation, Transfection, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Long-Term Synaptic Depression, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, HEK293 Cells, Death-Associated Protein Kinases

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