Review
Glycogen synthase kinase 3: an emerging therapeutic target

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Abstract

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a key target in drug discovery. It has been implicated in multiple cellular processes and linked with the pathogenesis of several diseases. GSK-3 inhibitors might prove useful as therapeutic compounds in the treatment of conditions associated with elevated levels of enzyme activity, such as type 2 diabetes and Alzheimer's disease. The pro-apoptotic feature of GSK-3 activity suggests a potential role for its inhibitors in protection against neuronal cell death, and in the treatment of traumatic head injury and stroke. Finally, selective inhibitors of GSK-3 could mimic the action of mood stabilizers such as lithium and valproic acid and be used in the treatment of bipolar mood disorders.

Section snippets

GSK-3 regulation

The GSK-3 enzyme and its unique properties have been described in recent comprehensive reviews 1, 2, 3. Mammalian GSK-3 exists as two isoforms, α and β, sharing 98% homology in their catalytic domain. Both isoforms are ubiquitously expressed in cells and tissues, and have similar (although not identical) biochemical properties. Unlike most protein kinases, GSK-3 is constitutively active in cells, and its activity can be inhibited by a variety of extracellular stimuli, including insulin,

Role of GSK-3 in insulin resistance and diabetes

Insulin resistance is an early change associated with the onset of non-insulin-dependent diabetes mellitus (NIDDM) or type 2 diabetes. The major defect in insulin resistance is the inability of peripheral tissues, such as muscle, liver and fat, to respond normally to physiological concentrations of insulin. Since one of the major characteristics of diabetic muscle is the severe inhibition of glycogen synthase and the loss of glycogen synthesis [20], it is reasonable to assume that a defect in

GSK-3 and tau

GSK-3 interacts with several neuronal proteins that are directly linked with Alzheimer's disease (AD). The microtubule-associated protein tau, a neuron-specific structural protein abundant in the brain, is a major component of neurofibrillary tangles, which are an intraneuronal aggregate of paired helical filaments (PHFs) and one of the most notable neuropathological hallmarks of AD, as reviewed in Ref. [34]. The tau protein in neurofibrillary tangles (also termed PHF-tau) is

GSK-3 and bipolar disorder

A notable recent development is the implication of a role for GSK-3 in psychiatric disorders. Lithium ions, used as a primary mood stabilizer in the chronic treatment of patients with bipolar disorder, were shown to be a selective inhibitor of GSK-3, as reviewed in Ref. [53]. A series of studies demonstrated that lithium ions mimic the loss of GSK-3 activity in intact cells. Lithium was shown to cause activation of glycogen synthesis [54], stabilization and accumulation of β-catenin [55],

GSK-3 inhibitors: a potential therapeutic approach

The paradigm that GSK-3 acts as a suppressor in signaling pathways points to a potential role for GSK-3 inhibitors in therapeutic interventions. Such inhibitors might be useful in pathological conditions associated with abnormally increased levels of GSK-3 activity such as type 2 diabetes and AD. In addition, specific inhibitors of GSK-3 mimic the therapeutic action of the mood stabilizers lithium and valproic acid and might therefore be plausible drugs in treating patients with bipolar

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