Abstract
Mitogen-activated protein (MAP) kinases are a central component in signaling networks in a multitude of mammalian cell types. This review covers recent advances on specific functions of p38 MAP kinases in cells of the central nervous system. Unique and specific functions of the four mammalian p38 kinases are found in all major cell types in the brain. Mechanisms of p38 activation and downstream phosphorylation substrates in these different contexts are outlined and how they contribute to functions of p38 in physiological and under disease conditions. Results in different model organisms demonstrated that p38 kinases are involved in cognitive functions, including functions related to anxiety, addiction behavior, neurotoxicity, neurodegeneration, and decision making. Finally, the role of p38 kinases in psychiatric and neurological conditions and the current progress on therapeutic inhibitors targeting p38 kinases are covered and implicate p38 kinases in a multitude of CNS-related physiological and disease states.
Highlights
Extracellular and environmental stimuli need to be integrated for adequate cellular and organismal responses
The last two decades of research have seen p38 kinases move from stress-activated kinases to signal transducers in multiple physiologic and pathophysiologic functions
This is true for cells of the central nervous system, where specific functions of p38 kinases were revealed in all major cell types contributing to brain physiology, cognition and behavior as well as disease processes
Summary
Extracellular and environmental stimuli need to be integrated for adequate cellular and organismal responses. Signal transduction is a key mechanism to translate stimuli into intracellular responses that converge in alterations in gene expression, of cellular shape and motility, and of metabolic activity (Hynes et al, 2013). Mitogen-activated protein (MAP) kinases are central to multiple signal transduction pathways across a variety of cell types, including cells of the central and peripheral nervous systems (Morrison, 2012), and are evolutionarily conserved across phyla (Widmann et al, 1999). The active site is covered by the activation loop, which undergoes dual phosphorylation resulting in conformation change, permitting access of substrates to the active site and full kinase activation (Figure 1B)
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