Excitotoxicity Flashcards
Excitatory amino acids
Glutamate (mostly)
Aspartate (often found with glutamate)
2 things that play a vital role in our functioning, but are also responsible for the mechanism of excitotoxicity
Ca
O2
Metabolic and NT pools of Glutamate
are strictly separated
What (general) types or receptors can be activated by EAA?
ionotropic
metabotropic
What are the two types of Ionotropic receptors that EAA bind to
NMDA receptors
non NMDA receptors
What ion is associated with the NMDA receptor?
Ca2+
What are (3) modulatory sites for the NMDA receptor
glycine binding site
Mg2+ binding site
PCP binding site
________ is a coagonist for the NMDA receptor
glycine
presence of glycine required for eaa to have effect
glycine cannot open channel on its own
_____ has to be displaced for the NMDA channel to be open
Mg2+
blocks the channel from the inside
cell must depolarize for MG to leave
Describe the characteristic epsp caused by the NMDA receptor
slow onset
longer duration
what is responsible for the slow onset of the epsp of the NMDA receptor
have to remove Mg from the channel
what is responsible for the long duration of the NMDA epsp
Ca2+ conductance
what ion does the non-NMDA receptor transmit
Na
what are two subtypes of the non NMDA receptor?
AMPA receptors
Kainate receptors
name two differences between the AMPA and kainate receptors
kainate can transmit some Ca
AMPA has a benzodiazapine site that inhibits its response to NT
What type of epsps do non NMDA receptors produce
typical epsp
explain why non NMDA receptors are often localized at the same synapse as NMDA receptors
eaa can bind the non-NMDA receptor, allowing Na to flow into the cell. That causes depolarization, which can knock the Mg out of the NMDA channel. Now, if eaa binds to the NMDA receptor, Ca can now flow through the channel
Where are metabotropic EAA receptors located
pre and post synaptically
What is the purpose of metabotropic EAA receptors located on the presynaptic membrane
modulate NT release.
What is the function of EAAs and non-NMDA receptors in the CNS
think PRIMARY AFFERENTS (sensory) and PREMOTOR (upper neurons)
Overall function of EAA
major excitatory system in the CNS
Function of the EAA - non - NMDA receptors
PRIMARY AFFERENTS
premotor (upper motor neurons)
FUnctions of the EAA - NMDA receptors
long term changes in synaptic strength
learning and memory
Functions of the EAA - metabotropic receptors
learning and memory
motor systems
Getting rid of EAA - neurons AND glia
uptake systems
Na dependent secondary active transport
HIGH AFFINITY
Getting rid of EAA - Glia only
convert to glutamine and release into the ECF ( glutamine can’t bind glutamate receptors)
neurons can then take up the glutamine and convert it to glutamate and repackage it into vesicles.
recycling process of glutamate
glutamate released into synaptic cleft as NT
glia pick up excess glutamate, convert it to glutamine, and release it
glutamine is taken up by neurons and converted to glutamate
glutamate is repackaged into vesicles to be used as a NT
EAA and NO
what receptor and what is the function
NMDA receptors
allow an influx of Ca which binds to calcineurin.
calcineurin activates NOS, which makes NO
How does NOS make NO
NOS (stimulated by calcineurin+Ca) cleaves arginine into
NO and citrulline
Neural functions of NO
longterm potentiation and memory
cardiovascular and respiratory control
How can NO be toxic
leads to production of free radicals
these not only kill invading bacteria, but can also kill other cells
Excitotoxicity definition
proposed to explain continuing neuronal death after an ischemic event
based on possibility that overstimulation of EAA system can cause cell death even in neurons that were not ischemic/hypoxic/anoxic
Excitotoxicity - strongly associated with (strong evidence of involvement in)
cerebral ischemia/stroke
hypoxia or anoxia
mechanical trauma to CNS
hypoglycemia
Excitotoxicity - substantial evidence of involvement in
epilepsy
What happens in the area most directly affected by ischemia (the anoxic core)?
oxygen deprivation
cells unable to meet metabolic needs (no glucose, no atp)
depolarization
within 4 minutes, ATP goes to zero. NaKatpase shuts off, Vm depolarizes, and EAA are released.
In excitotoxicity, what are two reasons we have high levels of EAA
Excessive EAA release,
unable to reuptake EAA (remember reuptake is Na dependent)
In excitotoxitity, explain what happens to the post synaptic cell
excess binding of EAA to NMDA receptors leads to increased CA influx excess calcium activates: - phospholipase A2 - calcineurin (phosphatase) - mu calpain ( protease) - apoptotic pathway
excess activation of these enzymes disrupts normal cellular function
In excitotoxicity, how does activation of phopholipase A2 disrupt normal cellular funciton
releases arachidonate from membrane (chews up membrane=physical damage to membrane)
arachidonate acts on RyR on ER, causing further release of Ca from intracellular stores ( “unfolded protein response” and activation of eIF2a-kinase)
impairs function of mitochondria
In excitotoxicity, how does activation of mu-calpain (protease) disrupt normal cellular function
proteolysis
esp. SPECTRIN = more structural damage to the cell
EIF4G (important in protein syntehsis)
others (metabolic imparement)
In excitotoxicity, how does activation of calcineurin disrupt normal cell function
calcineruin is a phosphatase
activates NOS
increases NO synthesis
how does the disruption of mitochondrial membrane due to excess Ca activate apoptosis
releases cytochrome C and Caspase 9
cyt C= marker that something dangerous is going on
Caspase 9= activates caspase 3, which is the major proapoptotic signal.
Caspase 3= proteolytic enzyme, apoptotic.
Reperfusion Injury - oxygen returns to ischemic neuron
neuron is no longer “normal” –> much of this O2 will end up as a free radical somewhere (peroxides)
can kill neurons already damaged from ischemic event AND other neurons
Reperfusion injury - O2 returns to mitochondria
If the mitochondria can make ATP it will, but the enzymes in the neuron that are currently activated arent NORMAL
Kinases will take the ATP and convert it to ADP and PO4
PO4 available for phophoyrlation, further modifying enzyme action
phosphorylation of EIF2a-kinase leads to a decreas in protein synthesis and activates caspase 3 which increases apoptotic signalling
How does NO add to the damage in the excitotoxicity cascade
in high quantity, neuronal NO can act directly on the capillary endothelial cells, causeing damage and edema
Prevention of excitotoxicity
difficult at best (this process happens starting at 4 minutes)
to date most experimentally successful treatments are pre-treatments that focus on the NMDA receptors.
