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

Glycogen synthase kinase 3 beta (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3 beta 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, GSK3 beta 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 GSK3 beta 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 GSK3 beta. Here, we discuss the direct and indirect mechanisms by which GSK3 beta phosphorylates voltage-gated Na+ channels (Na(v)1.2 and Na(v)1.6) and voltage-gated K+ channels (K(v)4 and K(v)7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3 beta activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3 beta-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.