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Necrosis and apoptosis are two distinct types of mechanisms that mediate ischemic injury. But a signaling point of convergence between them has yet to be identified. Here, we show that activated death-associated protein kinase 1 (DAPK1), phosphorylates p53 at serine-23 (pS23) via a direct binding of DAPK1 death domain (DAPK1DD) to the DNA binding motif of p53 (p53DM). We uncover that the pS23 acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus, pS23 induces the expression of proapoptotic genes, such as Bax, whereas in the mitochondrial matrix, pS23 triggers necrosis via interaction with cyclophilin D (CypD) in cultured cortical neurons from mice. Deletion of DAPK1DD (DAPK1DDΔ) or application of Tat-p53DM that interrupts DAPK1-p53 interaction blocks these dual pathways of pS23 actions in mouse cortical neurons. Thus, the DAPK1-p53 interaction is a signaling point of convergence of necrotic and apoptotic pathways and is a desirable target for the treatment of ischemic insults. [ABSTRACT FROM AUTHOR]

Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1PV) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PV synaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECIIPN contributes to a memory loss in AD and hence warrants a promising target for the treatment of AD. [ABSTRACT FROM AUTHOR]

EPAC (Exchange Proteins Activated by cAMP) regulates glutamate transmitter release in the central neurons, but a role underlying this regulation has yet to be identified. Here we show that EPAC binds directly to the intracellular loop of an ATP-sensitive potassium (KATP) channel type-1 sulfonylurea receptor (SUR1) receptor consisting of amino acids 859 - 881 (SUR1 859-881). Ablation of EPAC or expression of SUR1 859-881, which intercepts EPAC-SUR1 binding, increases the open probability of KATP channels consisting of the Kir6.1 subunit and SUR1. Opening of KATP channels inhibits glutamate release and reduces seizure vulnerability in adult mice. Therefore, EPAC inter-action with SUR1 controls seizure susceptibility and possibly acts via regulation of glutamate release. [ABSTRACT FROM AUTHOR]