Next, we review the abnormal signaling pathways and proteins found in bipolar patients, who generally have abnormally high intracellular Na<sup>+</sup> and Ca<sup>2+</sup> concentrations, high G-protein levels, and hyperactive phosphatidylinositol signaling and glycogen synthase kinase-3β (GSK3β) activity.
Our data imply GSK3β activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3β involves modulation of HCN4 level and the synaptic AMPA receptors pool.
This study demonstrates that hyper-insulinemia increases glutamate excitotoxicity which could be attributed to activation of GSK-3β and increased expression of PICK1.
Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch.
In fact GSK-3β is considered the main kinase which catalyzes the microtubule-associated protein tau hyper-phosphorylation and the neurofibrillary tangles (NFT) in vitro and in vivo, The first classes of GSK-3β inhibitors were classified as ATP-competitive and, therefore, they lack of an efficient degree of selectivity over other kinases.
However, cotinine failed to restore impaired cognition in GSK3β knockin mice, in which a serine9-to-alanine9 mutation blocks the inhibitory serine phosphorylation of GSK3β, causing GSK3β to be hyperactive.
Decreased function of the lysosome, an organelle required for autophagy and AMPK, have been associated with hyperactivity of glycogen synthase kinase 3β (GSK3β).
More importantly, persistent activation of Wnt signaling through Wnt ligands, or inhibition of negative regulators of Wnt signaling, such as Dickkopf-1 (DKK-1) and glycogen synthase kinase-3 β (GSK-3 β ) that are hyperactive in the disease state, is able to protect against A β toxicity and ameliorate cognitive performance in AD.