Protein phosphorylation and the regulation of mRNA translation following cerebral ischemia

This chapter discusses the changes in protein phosphorylation following ischemia, with particular reference to the regulation of the initiation of protein synthesis. Transient cerebral ischemia seems to induce a post-ischemic imbalance between protein kinase and protein phosphatase activities, leading to a net dephosphorylation of proteins in the vulnerable neurons. This imbalance may lead to the persistent changes in processes crucial for neuronal survival such as post-ischemic protein synthesis. The depression of protein synthesis after an ischemic insult most probably is because of a decreased guanine nucleotide exchange factor (GEF) activity, leading to a limited availability of eukaryotic initiation factors (eIF-2) for initiation complex formation. The inhibition of GEF activity in the vulnerable regions could in turn be because of dephosphorylation of GEF, possibly because of tyrosine phosphatase activation and a decreased casein kinase II activity. Post-ischemic inhibition of protein kinase C and calcium calmodulin kinase II may in addition depress eIF-4 activity leading to a selective translation of mRNA such as heat shock mRNA