GSK3b the pacifier
A surprising function of the GSK3b (which is often implicated in psychiatric disorders) – downregulation of HIF1 (the protein signalling about hypoxia).
My new understanding of GSK3b is that it works as a pacifier!
However something goes wrong in disorders when overactive GSK3b does more damage than good.
Metaphorical explanation
HIF1 is the alarm system that sends alert to many organizations such as fire department, police, hospital, etc.
HIF1 is triggered by low oxygen and other similar factors that create a risk of dying for the cell.
Nrf2 - a department that coordinates prevention and recovery from emergency situations receives the alert from HIF1 and initiates deployment of rescue teams and equipment.
PGC1a - an energy control department that controls different sources of energy production and can cut off energy supply from the units that can wait till the end of the recovery from disaster. It also receives the signal from HIF1 and switches energy consumers and suppliers into “emergency state”.
There is also a timer mechanism, that involves PI3K/Akt protein signalling, which is used when hypoxia starts to stop the pacifier (GSK3b) from preventing emergency teams from doing their work.
But when hypoxia lasts too long, PI3K level is depleted and it can’t hold the pacifier any more.
GSK3b gets reactivated (in fact, it has ability to activate itself when nobody tells it to sit tight).
The pacifier deactivates Nrf2 (the coordination center) and commands the energy control unit to get back to normal state (by inhibiting activation of PGC1a).
It also makes HIF1 to disappear, so everything should come to a normal, calm life by the action of GSK3b.
In a situation of high load of glucose GSK3b marks IRS1 (Insulin receptor substrate 1) for destruction, which causes insulin resistance (R2). It’s a way to stop glucose from coming in when the cell needs to “calm down”.
It’s only in psychiatric disorders when all emergency teams can’t mitigate the problem, the pacifier’s good work causes problems, because the normal life can’t resume until the initial problem is resolved completely.
Like with an actual pacifier - when a baby is hungry, pacifier may reduce the noise, but won’t feed the baby.
Same with GSK3b.
Next thoughts
Lithium replaces Magnesium within GSK3b, making it unable to do its job, resulting in increased stress-response of the cell (which may actually fix the problem if it gets all the tool).
Alternative description: GSK3b is a law that prohibits policemen to shoot bad guys, setting a limit of what can be done to them. Why? Potentially to prevent misfires and killing the cell itself (e.g. genetic defect that results in overactivation of Nrf2 leads to immunodeficiency).
It seems that in psychiatric disorders with overactive GSK3b (OCD, bipolar, schizophrenia) the suppressing power of GSK3b exceeds normal needs of the cell and impairs healthy function of the emergency teams (Nrf2, etc) because something doesn’t tell GSK3b to slow down. Some signal doesn’t come through.
My next hypothesis is that it can be chromium deficiency.
Why? because chromium (as chromodulin) is required to amplify PI3K/Akt pathway - the one that keeps GSK3b in check (e.g. in response to insulin and other signals).