Abstract:

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that has two isoforms encoded by two different genes, GSK-3α and GSK-3β, in mammals. GSK-3 has several sites of serine and tyrosine phosphorylation. Its activity is negatively regulated by phosphorylation of serine 21 for GSK-3α and serine 9 for GSK-3β, while it is positively regulated by phosphorylation of tyrosine 279 for GSK-3α and tyrosine 216 for GSK-3β. GSK-3 was initially found to be an important component of glycogen metabolism. However, recent studies have revealed that GSK-3 is a multifunctional kinase in various cell types, including neural cells. GSK-3α and GSK-3β are highly expressed in neural tissues such as the cerebral cortex, the hippocampus, the cerebellum, and the spinal cord. In particular, GSK-3β is elevated in the aged hippocampus, and more abundant than GSK-3α in rodents. Also, GSK-3β is highly expressed in neurons and astrocytes in the developing brain and spinal cord. Localized inhibitionof GSK-3 activity at the axon terminal is required for axon growth during development and regeneration after injury. Meanwhile, phosphorylation by GSK-3 activates some unprimed-substrates such as MAP1B, which stabilizes microtubules for axon extension. This is why global inhibition of GSK-3 at a high degree using pharmacological inhibitors or genetic elimination of both isoforms suppresses axon growth also a master regulator of neural stem cell proliferation and differentiation. Elevated GSK-3 activity is correlated with neuronal death. For example, overexpression of GSK-3β significantly increases neuronal cell death, and pharmacological inhibition of GSK-3 promotes the survival of several types of neural cells. Therefore, GSK-3 is a major factor in many facets of neural cell regulation, such as neurogenesis, neural stem cell proliferation, neural cell death, neuronal differentiation, and gliogenesis.