Glycogen synthase kinase 3 (GSK-3) (GSK-3 (commonly used); also referred to as GSK3 or GSK3α/GSK3β for its isozymes[1][2][4][7])

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase originally named for its ability to phosphorylate and inhibit glycogen synthase. It exists as two closely related isoforms in mammals, GSK-3α and GSK-3β, which are encoded by separate genes and have both overlapping and distinct roles. GSK-3 is a pivotal regulator in diverse signaling networks including insulin, Wnt, and neurotrophic pathways. It directly phosphorylates more than 100 different substrates, notably the microtubule-associated protein tau, a link central to the pathogenesis of Alzheimer’s disease and related tauopathies. Dysregulation of GSK-3 is implicated in numerous disorders ranging from metabolic diseases to neurodegeneration and psychiatric illness. GSK-3 has therefore been pursued as a drug target, with both clinical and preclinical inhibitors identified, though therapeutic development is complicated by the enzyme’s ubiquitous expression and pleiotropic functions[1][3][4][6][7].

Other names

GSK-3GSK-3α (glycogen synthase kinase 3 alpha)GSK-3β (glycogen synthase kinase 3 beta)Tau protein kinase I (older term, specifically for GSK-3β in the context of tau phosphorylation)[7]Serine/threonine-protein kinase GSK-3

Inhibitors block GSK-3’s kinase activity, often by competing for ATP binding or by allosteric modulation, leading to reduced phosphorylation of physiological substrates, especially tau and glycogen synthase[6]. For lithium, inhibition is via competition for magnesium at the active site[1].