Control of neuronal excitability by GSK-3beta: Epilepsy and beyond

Glycogen synthase kinase 3beta (GSK-3β) is an enzyme with a variety of cellular functions in addition to the regulation of glycogen metabolism. In the central nervous system, different intracellular signaling pathways converge on GSK-3β through a cascade of phosphorylation events that ultimately con...

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Veröffentlicht in:Biochimica et biophysica acta. Molecular cell research 2020-09, Vol.1867 (9), p.118745-118745, Article 118745
1. Verfasser: Jaworski, Tomasz
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Sprache:eng
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Zusammenfassung:Glycogen synthase kinase 3beta (GSK-3β) is an enzyme with a variety of cellular functions in addition to the regulation of glycogen metabolism. In the central nervous system, different intracellular signaling pathways converge on GSK-3β through a cascade of phosphorylation events that ultimately control a broad range of neuronal functions in the development and adulthood. In mice, genetically removing or increasing GSK-3β cause distinct functional and structural neuronal phenotypes and consequently affect cognition. Precise control of GSK-3β activity is important for such processes as neuronal migration, development of neuronal morphology, synaptic plasticity, excitability, and gene expression. Altered GSK-3β activity contributes to aberrant plasticity within neuronal circuits leading to neurological, psychiatric disorders, and neurodegenerative diseases. Therapeutically targeting GSK-3β can restore the aberrant plasticity of neuronal networks at least in animal models of these diseases. Although the complete repertoire of GSK-3β neuronal substrates has not been defined, emerging evidence shows that different ion channels and their accessory proteins controlling excitability, neurotransmitter release, and synaptic transmission are regulated by GSK-3β, thereby supporting mechanisms of synaptic plasticity in cognition. Dysregulation of ion channel function by defective GSK-3β activity sustains abnormal excitability in the development of epilepsy and other GSK-3β-linked human diseases. •Multiple ion channels and neuronal excitability are regulated by GSK-3β.•Multiple mechanisms may drive aberrant GSK-3β activity in epilepsy.•Evidence from animal models supports role of GSK-3β in epilepsy.•Several antiepileptic drugs also inhibit GSK-3β.
ISSN:0167-4889
1879-2596
DOI:10.1016/j.bbamcr.2020.118745