Mitogen and stress response kinase‐1 (MSK1) mediates excitotoxic induced death of hippocampal neurones

Abstract

Activation of the mitogen-activated protein kinase (MAPK/ ERK) signal transduction pathway may mediate excitotoxic neuronal cell death in vitro and during ischemic brain injury in vivo. However, little is known, of the upstream regulation or downstream consequences of ERK activation under these conditions. Magnesium removal has been described to induce hyperexcitability and degeneration in cultured hippocampal neurones. Here, we show that neurotoxicity evoked by Mg 2+ removal in primary hippocampal neurones stimulates ERK, but not p38, phosphorylation. Removal of Mg 2+ also resulted in induction of the MAPK/ERK substrate mitogen-and stressresponse kinase 1 (MSK1) and induced phosphorylation of the MSK1 substrate, the transcription factor cAMP response element binding protein (CREB). Neuronal death and phosphorylation of components in this cascade were inhibited by the Raf inhibitor SB-386023, by the MEK inhibitor U0126, or by the MSK1 inhibitors H89 and Ro318220. Importantly, this form of cell death was inhibited in hippocampal neurones cultured from MSK1-/-mice and inhibitors of Raf or MEK had no additive neuroprotective effect. Together, these data indicate that MSK1 is a physiological kinase for CREB and that this activity is an essential component of activity-dependent neuronal cell death. Keywords: cAMP-responsive element binding protein, excitotoxicity, hippocampal neurones, mitogen and stressresponse kinase-1, mitogen-activated protein kinase, neuroprotection.

N-Methyl-D-aspartate and Brain-Derived Neurotrophic Factor Induce Distinct Profiles of Extracellular Signal-Regulated Kinase, Mitogen- and Stress-Activated Kinase, and Ribosomal S6 Kinase Phosphorylation in Cortical Neurons

“…Likewise, PC12 cells were exposed to vehicle or 10 ng/ml NGF for 10 min and then processed for Western blotting with anti-pERK antibody (d), anti-pMSK1 antibody (e) or anti-p90RSK antibody (f). The finding that NMDA receptor activation leads to MSK1 phosphorylation is highly relevant in the context of a recent report demonstrating that increased MSK1 phosphorylation is observed during excitotoxicity in cultured neurons and that the activation of MSK1 may, in fact, contribute to the neurotoxicity observed (Hughes et al, 2003). Neurotoxicity in this model is linked to excessive glutamate receptor activation, including activation of NMDA receptors.…”

MSK regulate TCR‐induced CREB phosphorylation but not immediate early gene transcription

“…MSK1 and MSK2 have previously been shown to be critical for both CREB phosphorylation and the induction of CREB-dependent IE genes downstream of ERK1/ 2 and p38 MAPK activation in neurons, ES cells, fibroblasts and macrophages [8,9,38,39]. Previous studies using small molecule inhibitors have suggested a role for a PKC -Raf -ERK -RSK2 pathway in CREB phosphorylation downstream of TCR activation in T cells [31,33].…”

Mitochondrial dynamics in the regulation of neuronal cell death

“…In neurons, chronic activation of ERK at the nucleus induced by potassium withdrawal triggers non-classical caspase 3 independent cell death that is characterized by plasma membrane damage and nuclear condensation [119]. Activation of ERK has also been shown to be a key mediator in excitotoxicity [120] and ROS [121,122]. By inhibiting ERK activation, Mfn2 may also inhibit neuronal cell death independent of mitochondrial fusion (Fig.…”