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  • Activating GSK signaling to inhibit PK signaling during

    2021-05-28

    Activating GSK3β signaling to inhibit PK signaling during ischemia/reperfusion (I/R) is protective of WM ischemic injury. Glycogen synthase kinase (GSK3), which was the first substrate identified for AKT [44], is inhibited by AKT phosphorylation at positions S9 and S21 [45]. When GSK3β is active, it is known to promote the inactivation and degradation of its substrates [45]. GSK3β substrates also have to be phosphorylated at another site (i.e., “primed”) by another PK in order for GSK3β to phosphorylate them [45]. We have shown that CK2/AKT1/GSK3β signaling is present in HEK cells as well as in the oligodendrocyte cell line MO3.13. In addition, we have shown that the CK2/AKT/GSK3β axis is present in MONs. Specifically, OGD/reperfusion inactivates GSK3β  by increasing GSK3βS9 phosphorylation, which is attenuated by CX-4945 (Fig. 2D and E). Therefore, GSK3β activation in WM following OGD/reperfusion is associated with protection from ischemic injury. This later result is indeed surprising since in most cells, including neurons and OPCs, GSK3β inactivation is associated with increased survival and prevention of apoptosis [46,47]. However, in liver cells, GSK3β deletion increases cell death and apoptosis [48,49]. Thus, an alteration in signaling may be distinctive in different cells, thus accounting for the variable outcomes on cell survival between GM and WM with ischemia. We therefore propose that the protective effect of CK2 inhibition is partly mediated by a reduction in the inhibitory effect of CK2/AKT on GSK3β, thus Chlorpromazine HCl resulting in its activation. Furthermore, activated GSK3β can then inactivate its substrates, which are themselves substrates and primed by other PKs activated by I/R, thus increasing the number of PKs whose signaling is inhibited. Therefore, this predisposes a state of energy conservation in WM when ATP is momentarily unavailable.
    CK2 signaling during ischemia in Chlorpromazine HCl GM In GM, CK2 signaling can be either protective or damaging. For example, in a model of transient forebrain ischemia, the preservation or activation of CK2 activity was proposed to be important for neuronal survival after cerebral ischemia [8]. Specifically, It was reported that the regions vulnerable to ischemia showed a decrease in CK2 activity, whereas resistant regions were associated with an increase [8]. In contrast, in a model of global ischemia, an increase in CK2 activity in the dentate gyrus was reported [50]. Further investigation into the impact of transient cerebral ischemia and the role of CK2 signaling in a mouse model of ischemia (MCAO [51]) revealed that MCAO was associated with a decrease in CK2 (α- and α’) levels and activity. On the other hand, the changes in CK2 activity following ischemia varied as a function of time such that the reduction in CK2 levels was attenuated at 1 h and 3 h, remained unchanged at 6 h and 12 h, and was ∼60% below normal at 24 h and 48 h. Inhibition of CK2 with tetrabromocinnamic acid (TBCA) was associated with an increase in GM injury. And finally, using an MCAO model and the same experimental approach as Kim et al. [51], three other reports have concluded that CK2 signaling is protective of GM from ischemic injury [[52], [53], [54]]. Overall these studies suggest that neuronal responses to CK2 signaling vary depending upon the experimental model used. Could the experimental design that prolongs CK2 inhibition alter the outcome in ischemic experiments [55]? It is possible that neuronal injury observed with TCBA (MCAO model) and siRNA (cortical neuronal culture model) was caused by the duration of the reduction in CK2α protein levels/activity, since decreased CK2 activity for an extended period of time mediates cell death in non-neuronal cells [56]. In addition, the CK2 inhibitor used may have been injurious because some CK2 inhibitors have been shown to generate ROS [57]. Future experiments using a MCAO model subjected to a shorter duration of CK2 signaling inhibition using a different CK2 inhibitor, such as CX-4945, need to be conducted in order to answer these questions.