DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific

Publication date: 13 June 2017
Source:Cell Reports, Volume 19, Issue 11
Author(s): Dayton J. Goodell, Vincent Zaegel, Steven J. Coultrap, Johannes W. Hell, K. Ulrich Bayer
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 Ca²⁺/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 Ca²⁺/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.

Graphical abstract

Teaser

Goodell et al. find that calcineurin (CaN)-dependent activation of the death-associated protein kinase 1 (DAPK1) is required for a form of long-term synaptic plasticity, LTD. Specifically, DAPK1 suppresses Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) synaptic accumulation and GluN2B binding during LTD, thus making these CaMKII mechanisms LTP specific.


http://ift.tt/2ssGPpj