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

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 (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) 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 neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.

Inhibition of Glycogen Synthase Kinase 3β Activity in the Basolateral Amygdala Disrupts Reconsolidation and Attenuates Heroin Relapse

“…GSK-3β is a isoform of GSK-3, extensively involved in memory processing. The regulation of GSK-3β can affect neural functions like synaptic plasticity, which is the foundation of learning and memory ( Banach et al, 2022 ; Li et al, 2022 ; Marosi et al, 2022 ). Also, GSK-3β regulates the structural and functional synaptic plasticity.…”

Crosstalk among WEE1 Kinase, AKT, and GSK3 in Nav1.2 Channelosome Regulation

“…This competition may be explained by GSK3 inhibitor XIII restoring a pool of active WEE1 by limiting its degradation mediated by GSK3 [25]. On the other hand, WEE1 and AKT either compete, possibly due to GSK3 inhibition conferred by triciribine [26,27], or synergize through mechanisms similar to those reported in cancer cells [23].…”

“…We have no evidence that AKT directly phosphorylates FGF14 or Nav1.2. However, AKT inhibits GSK3 (both isoform  and  ) via an inhibitory phosphorylation at S9/S21 [26,27], and GSK3 regulates WEE1 through ubiquitination [25]. Additionally, there is evidence for WEE1 inhibitor synergy with AKT inhibitors [23], suggesting a positive feedback loop.…”

“…Although not much is known about WEE1 regulatory activity in postmitotic differentiated cells such as neurons, studies from the cancer field indicate that WEE1 activity is closely linked to AKT [23] and GSK3 [24]. WEE1 can be controlled by GSK3, which regulates its degradation [25], and can work synergistically with AKT [23], a well-known upstream suppressor of GSK3 [26,27]. These intricate positive and negative feedback loops between WEE1, GSK3, and AKT may also take place in neurons, indirectly impacting FGF14/Nav1.2 complex formation and Nav1.2 channel activity.…”

The role of glycogen synthase kinase 3 beta in neurodegenerative diseases

“…These isoforms share a striking 97% amino acid sequence identity within the catalytic domain and 84% overall amino acid sequence similarity, suggesting potential common biological functions. For example, they regulate cell signaling, participate in biological metabolism, cell growth, proliferation, and differentiation, and are critical regulatory factors in many neurodevelopmental processes ( Marosi et al, 2022 ). GSK-3β exhibits high levels of expression in the central nervous system (CNS; Yao et al, 2002 ).…”