GSK-3 was initially identified as a kinase activity that phosphorylates and inactivates glycogen synthase. Being the third kinase discovered with this activity towards glycogen synthase, it was aptly named glycogen synthase kinase-3.

Glycogen Synthase Kinase 3 (GSK-3) is a serine/threonine kinase that was originally identified as a key regulator of glycogen synthase in glycogen metabolism and insulin responses. GSK-3 is highly conserved from the Drosophila homologue zeste-white3/shaggy to humans. Despite it’s name, GSK-3 is now known to be a multifunctional kinase with a broad range of targets and a key role in several signaling cascades. GSK-3 α and β are ubiquitously expressed and both are highly expressed in the brain during development in both neurons and in glia. In mammals, GSK-3 has two isoforms, GSK-3α and GSK-3β that are 85% identical and have a catalytic domain similarity of over 90%. The main differences between isoforms lie outside the catalytic domain in the N-terminus, where the α isoform has an N-terminal extension that may regulate nuclear transport. Mice and humans have an alternatively spliced variant of GSK-3β of unknown function that contains a 13 amino acid inserted sequence in the kinase domain and is highly expressed in the nervous system.

Differences in isoform function are evident in mouse models where GSK-3α knockout mice are viable while GSK-3β knockouts are embryonic lethal. These results suggest that in many cell types GSK-3β is the more important family member. However, it was found that one isoform can clearly compensate for the other and that deletion of both isoforms is required to get a full picture of GSK-3 function in vivo.

GSK-3 Function in Mature Neurons and Human Diseases

Not surprisingly, GSK-3 exhibits important functions in mature neurons. For the most part this regulation has been studied in in vitro models. For example, pharmacological inhibition of GSK-3 decreases vesicular transport in axons by reducing making further understanding of its role in neural development an urgent priority. For example, abnormal GSK-3 activity may underlie mood disorders. Thus Lithium, a known GSK-3β inhibitor, is the mainstay of treatment for bipolar disorder. Additionally, the drug valproate, also sometimes used to treat mood disorders, is also an inhibitor of GSK-3 kinase activity.

GSK-3 may also be important in the pathogenesis of schizophrenia. Administration of antipsychotics, haloperidol or clozapine inhibits GSK-3 activity via ser9 phosphorylation. Additionally, a regulator of GSK-3, Disrupted-in-Schizophrenia 1 (DISC1) has been implicated as a major susceptibility factor for Schizophrenia. DISC1 functions in party by affecting the GSK-3 functions related to progenitor proliferation in both neonates and adults. Finally in peptides from amyloid precursor protein and the development of neurofibrially tangles composed of hyper-phosphorylated tau. Interestingly GSK-3 inhibition blocks the production of amyloid-β peptides suggesting that GSK-3 is required for normal amyloid precursor protein function. Additionally, GSK-3 strongly regulates the phosphorylation status of the MAP tau. Hyper-phosphorylated tau is found in the neurofibrially tangles in the brains of Alzheimer’s patients. Hyper-phosphorylated tau also underlies a class of neurodegenerative diseases called tauopathies.


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