Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases

Mate Marosi, Parsa Arman, Giuseppe Aceto, Marcello D’Ascenzo, Fernanda Laezza

Research output: Contribution to journalReview articlepeer-review

10 Scopus citations

Abstract

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav 1.2 and Nav 1.6) and voltage-gated K+ channels (Kv 4 and Kv 7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsy-chiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.

Original languageEnglish (US)
Article number4413
JournalInternational journal of molecular sciences
Volume23
Issue number8
DOIs
StatePublished - Apr 1 2022
Externally publishedYes

Keywords

  • GSK3β-mediated phosphorylation
  • intracellular fibroblast growth factors (iFGF)
  • neuronal excitability
  • neuronal plasticity
  • neuropsychiatric disorders
  • protein–protein interaction
  • sodium-and potassium-current
  • voltage-gated ion channels

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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