Lecture 5: Excitotoxicity (Karius) Flashcards
What are the 4 steps from hypoxia to inappropriate calcium presentation in the cell?
Hypoxia = no ATP for the Na/K ATPase
This causes action potentials.
In EAA neurons, this means EAAs enter the synapse and activate NMDA receptors (also, glial cells can’t clear EAA because of step 1).
NMDA receptors open and calcium rushes in.
Why is reperfusion damaging post-excitotoxicity?
Because the mitochondria are dysfunctional, they cannot use the oxygen in the area. This allows the oxygen to degenerate into free radicals and be cytotoxic.
What mitochondria do exist are providing ATP to damaging proteins, like proteases and caspase 3.
What is the role of calcineurin in excitotoxicity?
Calcineurin + all the extra calcium activates NO synthase, leading to inappropriate levels of NO in the area.
What 5 conditions have been associated with excitotoxicity?
Strokes
Global hypoxia/anoxia (eg. near drowning)
Traumatic brain injury
Hypoglycemia
Epilepsy
Excitotoxicity mediated calcium influx stimulates what two proteases which lead to structural impairment (rather than apoptosis)?
What do these two proteases do?
μ-calpain and phospholipase A
μ-calpain breaks down spectrin, and interrupts eIF4G, which damages protein synthesis.
Phospholipase A “chews on” phospholipids, creating an inappropriate amount of arachidonic acid - as well as causing structural damage.
What three things does phospholipase A mediated release of arachidonic acid cause in the cell during excitotoxicity?
Unfolded protein response: the arachidonic acid causes the release of Ca2+ from the mitochondria and endoplasmic reticulum, which causes the release of unfolded proteins.
The calcium release from the mitochondria causes caspase 9 and cytochrome C release from the mitochondria, which leads to an apoptotic cascade via caspase 9 to caspase 3
eIF2α-kinase becomes inapprpriately activated.
What two issues come from NO excess in excitotoxicity?
NO causes vast vasodilation and swelling, even to the point of herniation.
NO degrades rapidly into free radicals, which can be cytotoxic.
