excitotoxicity

Question 1

EAA (2)

Answer 1

Glutamate

Aspartate

Question 2

EAA location

Answer 2

most important excitatory NT system in brain

widely distributed throughout CNS

Question 3

NMDA receptor

Answer 3

EAA ionotropic receptor
needs both EAA and gly to open channel
Mg blocks channel at rmp (makes NMDA both ligand
and voltage-gated)
PCP binding site blocks channel
activated –> influx of Ca

Question 4

Non-NMDA receptor

Answer 4

EAA ionotropic receptor (primarily Na influx)
2 types:
AMPA (Benzodiazepines bind and reduce Na influx)
Glu/asp endogenous ligands
Kainate

Question 5

NMDA vs Non-NMDA

Answer 5

Non-NMDA: short onset, short duration epsp; depol.
caused by opening allows Mg in NMDA channels to
be released

primary sensory afferents

NMDA: long onset, long duration epsp

critical in long-term memory formation

Question 6

EAA metabotropic receptors

Answer 6

3 groups:
1: Gq coupled
2&3: Gi coupled

Pre-synaptic: control NT release
Post-synaptic: 
    Learning
    Memory
    Motor systems

Question 7

step 1 of excitotoxicity

Answer 7

depolarization of membrane
w/in 4 minutes of loss of blood flow:
O2 drops to 0 near mito, ATP production ceases
Na/K activity quickly drops
depol of neuronal cell membrane

Question 8

step 2 of excitotoxicity

Answer 8

APs

Question 9

step 3 of excitotoxicity

Answer 9

releasing EAAs throughout brain

into trough/cleft

Question 10

Limiting action of EAA

Answer 10

uptake is dependent on secondary active transport of Na

Question 11

Excitotoxicity

Answer 11

proposal: overstimulation of EAA system occurs after ischemia in the brain and is responsible for damage to neurons regardless of exposure to ischemia

Question 12

step 4 of excitotoxicity

Answer 12

activation of NMDA and non-NMDA receptors –> massive release of calcium enter post-synaptic cell

Question 13

Consequences of high intracell. Ca

Answer 13

Increase in Phospholipase A activity –> physical damage to membrane
arachidonic acid –> mito dysfxn, ER stops making
proteins, eIF2a-kinase activation

activation of calpain
proteolysis of structural proteins, enzymes (including
eIF4G – further protein synthesis problems)
leads to metabolic and structural impairment of
neurons

activation of calcineurin
excessive production of NO via activation of NOS

activation of apoptotic pathway
mito damage releases cyt c and Ca –> activate
caspase 3

Question 14

reperfusion injury

Answer 14

bringing o2 back to mito-impaired cells (mito can’t use the o2) –> production of free radicals (toxic)

kinases take ATP –> ADP + PO4 –> phosphorylations
–> eIF2a kinase phospho –> further decrease protein
synth –> further activate caspase 3 –> more apoptosis