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DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific.
Dayton J Goodell1, Vincent Zaegel2, Steven J Coultrap2
1Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Program in Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Cell Reports
|June 15, 2017
Summary
Death-associated protein kinase 1 (DAPK1) regulates synaptic plasticity by controlling Ca2+/calmodulin-dependent protein kinase II (CaMKII) binding to NMDA receptors. This mechanism is crucial for learning and memory, differentiating long-term potentiation from long-term depression.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Death-associated protein kinase 1 (DAPK1) is known to mediate neuronal cell death.
- Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), is critical for learning, memory, and cognition.
- Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation at T286 is essential for both LTP and LTD, mediating CaMKII binding to the NMDA receptor (NMDAR) subunit GluN2B.
Purpose of the Study:
- To investigate the role of DAPK1 in synaptic plasticity.
- To elucidate the regulatory mechanism of CaMKII synaptic accumulation during LTP and LTD.
- To determine how DAPK1 influences CaMKII binding to GluN2B and its functional consequences.
Main Methods:
- Investigated DAPK1 regulation of CaMKII activity and binding to GluN2B.
- Utilized competitive binding assays to assess DAPK1 and CaMKII interaction with GluN2B.
- Employed a pharmacogenetic approach to evaluate the necessity of DAPK1-mediated suppression of CaMKII/GluN2B binding for LTD.
Main Results:
- DAPK1 activation, dependent on calcineurin (CaN), suppresses CaMKII binding to GluN2B during LTD.
- DAPK1 competes with CaMKII for binding to GluN2B, blocking CaMKII synaptic accumulation during LTD.
- Ca2+/calmodulin negatively regulates DAPK1 binding to GluN2B, leading to DAPK1 removal during LTP and retention during LTD.
- Pharmacogenetic suppression of CaMKII/GluN2B binding confirmed it as a DAPK1-dependent function required for LTD.
Conclusions:
- DAPK1 plays a critical role in regulating synaptic plasticity by modulating CaMKII function.
- The differential regulation of DAPK1/GluN2B binding by Ca2+/CaM explains the opposing roles of DAPK1 in LTP and LTD.
- DAPK1-mediated suppression of CaMKII/GluN2B interaction is a key mechanism underlying LTD and cognitive processes.
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