Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that catalyzes the addition of a phosphate group (PO43−)
onto serine or threonine residue in a protein. It targets a plethora of substrates, including the Tau protein that plays a central role in
Alzheimer's disease and α-synuclein which is a key player in Parkinson's disease. GSK-3 has two isoforms: GSK-3α and GSK-3β. They can be inactivated through
the phosphorylation of a single residue: serine 21 for GSK-3α or serine 9 for GSK-3β. Akt (also called protein kinase B) is a major kinase capable of inactivating GSK-3
by phosphorylation on Ser-21/Ser-9.
Regulation of GSK-3 Activity
A few signaling pathways converge to the activation of Akt, resulting in GSK-3 inactivation (Figure 1).
Figure 1. Signaling pathways leading to activation of Akt, which in turn inactivates GSK-3 by phosphorylating Ser-21/Ser-9.
Trk stands for tyrosine (or tropomyosin) receptor kinase. One of its subtypes, TrkB, is the receptor of brain-derived neurotrophic factor (BDNF).
[Source: Wildburger and Laezza, 2012]
Alternatively, high level of Ca2+ ions may activate calpain to remove the N-terminal regulatory domain, rendering GSK-3 persistently active.
Lithium, a well-documented GSK-3 inhibitor, seems to exert its inhibitory function by binding to the cleaved GSK-3, as it can inhibit both full-length and cleaved GSK-3
(Goñi-Oliver et al., 2007).
Figure 2. GSK-3 may become persistently active after cleavage by calpain.
In addition to Ser-21/Ser-9, the GSK-3 activity is also regulated by the phosphorylation state of a tyrosine residue: Tyr-216 for GSK-3β or Tyr-279 for GSK-3α.
Phosphorylation of the tyrosine residue augments the GSK-3 activity. It can be catalyzed by the non-receptor tyrosine kinase Src
(Goc et al., 2014)
or Fyn (Lesort et al., 1999).
GSK-3 acts on a variety of proteins that play important roles in brain functions.
- Tau protein. Hyperphosphorylation of Tau by GSK-3 plays a crucial role in Alzheimer's disease.
- α-Synuclein. This protein is the major component of the pathological inclusion bodies
(called "Lewy bodies") in Parkinson's disease and Dementia with Lewy Bodies. Approximately 90% of α-synuclein found in Lewy bodies are phosphorylated at Serine-129 (S129)
(Sato et al., 2011;
GSK-3β has been shown to phosphorylate α-synuclein at S129 (Credle et al., 2015).
- CRMP2. GSK-3 may phosphorylate CRMP2 and disrupt its binding with tubulin.
This process could be implicated in Alzheimer's disease and bipolar disorder.
- Potassium channels. Under normal physiological conditions, opening of the potassium channel allows K+ ions to flow outward,
resulting in membrane hyperpolarization. This has inhibitory effect on neuronal firing. GSK-3 may phosphorylate and inactivate the potassium channel Kv7.2
(encoded by KCNQ2) (Wildburger and Laezza, 2012) or Kv4.2
(Scala et al., 2015). Thus, through its action on potassium channels,
GSK-3 may enhance excitability.
- Sodium channels. In contrast to potassium channels, the Na+ influx through sodium channels makes the membrane more depolarized,
which has excitatory effect on neuronal firing. The sodium channels, Nav1.6 and Nav1.2, are modulated by their association with the protein FGF14
(Laezza et al., 2009). GSK-3 may promote the association between the sodium channel and FGF14,
thereby enhancing excitability (Shavkunov et al., 2013).
- AMPA receptors. They conduct mainly Na+ ions. Elevated GSK-3 activity enhances the insertion of AMPA receptors
into the postsynaptic membrane, resulting in higher excitability (Wei et al., 2010;
Wildburger and Laezza, 2012).
Author: Frank Lee
First published: May 24, 2019