Review Article

The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease

Figure 1

Signalling pathways leading to the activation of p38 MAPK in neurons. (a) Inflammatory cytokines bind to specific receptors at the cell surface, which initiate a cascade of events promoting the activation of interleukin-1 receptor-associated kinase (IRAK), TNF receptor-associated factor (TRAF) 2/6 leading to the activation of MKKKs (TAK 1, ASK-1), and subsequently phosphorylation of MKK3 and MKK6, the upstream activators of p38 MAPK. (b) Release of glutamate from the presynaptic terminal can also activate p38 MAPK via a similar route. Binding of glutamate by the postsynaptic GI-mGluR receptors causes the activation of G-proteins, which promote the exchange of GDP with GTP of Rap 1. Rap 1 then initiates a cascade leading to the phosphorylation of MKK3/6 and p38 MAPK. The steps linking p38 MAPK activation to the internalisation of AMPA receptor (AMPAR) subunits observed during mGluR induced long-term depression are not yet known. Reports have suggested that binding of glutamate to NMDA receptors (NMDARs) also activates p38 MAPK. However, the molecular mechanism linking NMDAR activation to p38 MAPK phosphorylation is not yet known. The activated p38 MAPK signalling cascade has been shown to regulate AMPAR trafficking; however no substrate for this regulation has been described.
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