Figure 1
From: The p38α mitogen-activated protein kinase as a central nervous system drug discovery target
Diagrammatic outline of p38 mitogen-activated protein kinase (MAPK) pathways in glia and neurons. Disease-relevant stressors or stimuli can activate a variety of cross-talking and interacting signal transduction pathways, some of which can converge on activation of the p38 MAPK signaling cascades. For example, a typical p38 MAPK cascade consists of a three-tiered series of protein kinases: a MAPK (p38) and two upstream components (a MAPK kinase (MEK) and a MAPKK kinase (MEKK)) that activate the p38 MAPK by a series of activating phosphorylations. Activation of p38 MAPK and phosphorylation of its downstream substrates in activated glia (primarily microglia) can lead to up-regulation of proinflammatory cytokine production. Proinflammatory cytokines can act back on glia to stimulate multiple intracellular signaling pathways. Neurons can also respond to proinflammatory cytokine or other stressors/stimuli and activate neuronal p38 MAPK, culminating in neuron damage. The consequences of p38 MAPK activation in glia and neurons depend on the set of upstream signals, the isoform of p38 MAPK, the cell type, and the set of substrates that are stimulated.