thuuk
Iron
- Joined
- Jun 23, 2025
- Posts
- 224
- Reputation
- 157
Roids cause neurotoxicity through a TON of mechanisms, but excitotoxicity is one of the worst ones. In this thread I will cover one of the best solutions to it and explain what it even is + how PSD95 decoupling works. At the bottom theres a TL;DR if tiktok fried your brain 
WHAT EVEN IS EXCITOTOXICITY
WHAT IS THE PSD95 DOMAIN AND HOW DOES IT CONNECT TO EXCITOTOXICITY
HOW DO PSD95 DECOUPLERS COME INTO PLAY?
TL;DR:
PSD95 has different subtypes, one of them being PDZ2 which is insanely important for our purpose. It works by anchoring a protein near the NMDAR which normally releases NO to act like a finetuner but when chronically activated, what aas cause, it will cause aptosis and brain damage. When we decouple this entire process, we get rid of this risk
DISCLAIMER: NEUROTOXICITY IS CAUSED BY A LOT OF FACTORS, THIS ONE BEING ONLY ONE OF THEM!!!
WHAT EVEN IS EXCITOTOXICITY
Excitotoxicity is the process, where your NMDA Receptors (basically your receptors that control your thinking, LTP, learning, etc) constantly fire Calcium ions through them and thus activate a very delicate process. Now, in a normal brain all of this is needed for your brain to even function (I can also do a thread explaining NMDARs in depth if you guys want). But when its chronically activated, it causes severe aptosis and death of synapses + neurons.
WHAT IS THE PSD95 DOMAIN AND HOW DOES IT CONNECT TO EXCITOTOXICITY
The PSD95 domain is very complex, just like NMDARs, but it basically consists of three subtypes ; PDZ1 , PDZ2 and PDZ3. Every subtype of this domain has its own function, but for this thread we will focus on PDZ2 since thats the most important one for our purpose. Now, NMDARs are part of a huge protein network, consisting of a ton of different proteins and mechanisms, one of them being PSD95. Now, when the NMDAR (specifically a specific subunit of the NMDAR) binds to the PDZ2 domain, PDZ2 makes a protein called nNOS be very close to the receptor. nNOS is a protein "factory" basically that produces NO. Normally, this NO isnt harmful at all and even acts as a fine tuner for overall synapses and other NMDARs. It basically works like this, Ca rushes through the NMDAR, activating two different proteins: Calmodulin and CaMKII. CaMKII only phosphorylates (activates in this case) PSD95. Calmodulin sends a signal to nNOS because PDZ2 made it be so close to the receptor, to release the NO.
Little analogy: You can think of it like this ; the NMDAR is a ship and the PDZ2 domain is the harbour, while nNOS with families of people to go back to. Now, when the people want to go to the land after a trip, they have only one way of going to it ; through using the harbour. Otherwise they cant get to their families and make their family members happy (= release NO). They can only go to the land because the harbour connects it so close to the ship (PDZ2 connecting the nNOS close to the receptor).
Now, when the NMDAR gets chronically activated and chronically causes a Ca influx, Calmodulin obviously chronically activates nNOS mediated NO release. This then causes the NO to react with Superoxide which then reacts to Peroxynitite, causing protein, lipid and DNA damage ; direct aptosis.
Little analogy: You can think of it like this ; the NMDAR is a ship and the PDZ2 domain is the harbour, while nNOS with families of people to go back to. Now, when the people want to go to the land after a trip, they have only one way of going to it ; through using the harbour. Otherwise they cant get to their families and make their family members happy (= release NO). They can only go to the land because the harbour connects it so close to the ship (PDZ2 connecting the nNOS close to the receptor).
Now, when the NMDAR gets chronically activated and chronically causes a Ca influx, Calmodulin obviously chronically activates nNOS mediated NO release. This then causes the NO to react with Superoxide which then reacts to Peroxynitite, causing protein, lipid and DNA damage ; direct aptosis.
HOW DO PSD95 DECOUPLERS COME INTO PLAY?
PSD95 decouplers (the best one being Nerinetide), basically act like a decoy at the NMDAR/PDZ2 domain, causing nNOS to not be near the NMDAR and not causing excitotoxicity
TL;DR:
PSD95 has different subtypes, one of them being PDZ2 which is insanely important for our purpose. It works by anchoring a protein near the NMDAR which normally releases NO to act like a finetuner but when chronically activated, what aas cause, it will cause aptosis and brain damage. When we decouple this entire process, we get rid of this risk
DISCLAIMER: NEUROTOXICITY IS CAUSED BY A LOT OF FACTORS, THIS ONE BEING ONLY ONE OF THEM!!!
Last edited:
