The p38MAPK-MK2 Signaling Axis as a Critical Link Between Inflammation and Synaptic Transmission

Abstract

p38 is a mitogen-activated protein kinase (MAPK), that responds primarily to stress stimuli. p38 has a number of targets for phosphorylation, including MAPK-activated protein kinase 2 (MK2). MK2 primarily functions as a master regulator of RNA-binding proteins, indirectly controlling gene expression at the level of translation. The role of MK2 in regulating the synthesis of pro-inflammatory cytokines downstream of inflammation and cellular stress is well-described. A significant amount of evidence, however, now points to a role for the p38MAPK-MK2 signaling axis in mediating synaptic plasticity through control of AMPA receptor trafficking and the morphology of dendritic spines. These processes are mediated through control of cytoskeletal dynamics via the activation of cofilin-1 and possibly control of the expression of Arc/Arg3.1. There is evidence that MK2 is necessary for group I metabotropic glutamate receptors long-term depression (mGluR-LTD). Disruption of this signaling may play an important role in mediating cognitive dysfunction in neurological disorders such as fragile X syndrome and Alzheimer’s disease. To date, the role of neuronal MK2 mediating synaptic plasticity in response to inflammatory stimuli has not yet been investigated. In immune cells, it is clear that MK2 is phosphorylated following activation of a broad range of cell surface receptors for cytokines and other inflammatory mediators. We propose that neuronal MK2 may be an important player in the link between inflammatory states and dysregulation of synaptic plasticity underlying cognitive functions. Finally, we discuss the potential of the p38MAPK-MK2 signaling axis as target for therapeutic intervention in a number of neurological disorders.

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood–Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations

“…However, levels of pp65 and pAkt were little altered by BDL ( Figure 2 j). MAPK-activated protein kinase 2 (MK2) is directly associated downstream to pp38 [ 31 ]. Here, phosphorylation of MK2 was also monitored to reflect activation of p38 MAPK.…”

“…protein kinase 2 (MK2) is directly associated downstream to pp38 [31]. Here, phosphorylation of MK2 was also monitored to reflect activation of p38 MAPK.…”

Inflamma-MicroRNAs in Alzheimer’s Disease: From Disease Pathogenesis to Therapeutic Potentials

“…Aβ activates p38MAPK and leads to an increase in the amount of calcium influx and ROS, which leads to increased mitochondrial oxidative stress and promotes AD onset and progression (Kheiri et al, 2018). Moreover, p38MAPK is also involved in the pathogenesis of AD by promoting Tau phosphorylation (Sun Y. et al, 2017), thus reducing synaptic plasticity (Beamer and Corrêa, 2021) and activating microglia to release pro-inflammatory factors (Liu Q. et al, 2019). Astrocytes also play an important role in the pathogenesis of AD.…”

Anti-inflammatory effects of extracellular vesicles from Morchella on LPS-stimulated RAW264.7 cells via the ROS-mediated p38 MAPK signaling pathway

“…MAPK-activated protein kinase 2 (MK2) is an important downstream substrate of the p38 MAPK signaling pathway [53,54]. MK2 is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, gene expression regulation, and cell proliferation [55][56][57]. To further prove our results, we examined the expression of MK2, a protein downstream of the p38 MAPK signaling pathway.…”