Canedo-Antelo, M. , Matute, C. & Sánchez-Gómez, M. V.
Achucarro Basque Center for Neuroscience, CIBERNED and Department of Neurosciences, University of Basque Country (UPV/EHU), Leioa, Spain
Casein kinase 2 (CK2) is a ubiquitous serine-threonine kinase involved in a multitude of cellular processes through modulation of numerous substrates, mostly proteins related to cellular survival/death signaling. CK2 activity has been found to be significantly enhanced in many human and experimental pathologies and increasing evidence links CK2 to the dual function of pro-survival and apoptotic pathways. To analyze the role of CK2 in the functional control of survival/death, here we have investigated the involvement of CK2 in AMPA-induced excitotoxicity using rat cultured oligodendroglial cells. Thus, we observed that two CK2-specific inhibitors, TBB and DRB, attenuated mitochondrial dysfunction and subsequent cell death provoked by brief and moderate AMPA receptor stimulation in oligodendrocytes. Specifically, the CK2 inhibitors, through changes in the phosphorylation levels, modulated the Bcl-2 family protein activation and their redistribution between cytosol/mitochondria/nucleus, modifying the apoptotic properties of these molecules.
Additionally, the moderate stimulation of AMPA receptors in oligodendrocytes caused an early and potent increase in the phosphorylated-JNK levels, and JNK inhibitor SP600125 prevented the activation of BH3-only proteins and finally, protected oligodendrocytes from AMPA-induced excitotoxicity.
Together, these results show that CK2 and JNK-dependent pathways are key regulators of AMPA-induced phosphorylation/activation of Bcl-2 family proteins, mitochondrial dysfunction and cell death in cultured oligodendrocytes and suggest that modulation of this signaling may help in developing novel drugs with therapeutic potential for demyelinating diseases