glutamate comes from what
alpha-ketoglutarate
the metabolic and NT pools of glutamate are/are not strictly separated
are
aspartate comes from ___
- where is it the NT
oxaloacetate
visual cortex and pyramidal cells
what is the excitatory ionotropic receptor
NMDA receptor
what is the effect of NMDA receptor binding
allows Ca++ influx
glycine binding site
co-agonist
presence of glycine required for EAA to have effect
-on own cannot open channel
magnessium binding site on NMDA
inside channel
blocks channel, prevents influx of calium
-cell must open and depolarize in order for magnesium to be repelled out
3 modulator sites onf NMDA channel
glycine
mg++
PCP
PCP binding site
inside channel, deep to Mg++
blocks channel
no calcium allowed in
irreversible binding
NMDA receptor activation leads to what
what kind of onset and duration
EPSP
slow onset bc of process, getting magneium out
prolonged duration bc calcium is entering, it is bigger and slower
non-NMDA receptor influx
-2 subtypes
sodium influx (some: very small amount of calcium too)
AMPA
kainate
what inhibits the AMPA response to EAA
benzodiazepine
why is it important to have NMDA and non-NMDA receptors at the same post synaptic membrane
need to have sodium influx from non-NMDA to depolarize cell and allow for the sodium to repel Mg++ on the NMDA receptor so that calcium can rush in
which non-NMDA receptor allows a little bit of calcium into the cell as well as sodium
kainate
where is the NMDA receptor located
almost exclusively post synaptically
where is the location of metabotropic receptors for EAA
both pre and post synaptically
pre control release of NT
function of non-NMDA receptors
primary afferents
premotor (upper mn)
function of NMDA receptors
long term changes in synaptic strength
learning
memory
getting rid of the EAA: neurons and glia
2ndary active transport with sodium
-high affinity
getting rid of EAA: glia
convert glutamate to glutamine and release into ECF
-neurons take glutamine up and convert it back to gluatamate
when calcium influxes into cell from NMDA receptor opening what does it bind and what does this activate
binds calcineurin and activates NOS
-arginine–>NO
NO is ___ soluble and can work where
lipid
pre and post synaptic cells and also on neighboring cells
Neural functions of NO
long-term potentiation and memory
cardiovascular and respiratory control
how is NO toxic and what cells affected
can create free radicals
-cells that make NO have protective mechanisms against it but neighboring cells can be damaged bc they don’t have protection
EAA (glut/asp/taurine
Central location function ITR MTR other
central location: widespread spinal cord through cortex
fnct: primary afferents, motor activation of a-motor neuron
-soncsciousness, learning, memory
ITR: NMDA and Non-NMDA
MTR: yes
other: NOS activation and NO production
what happens in the area most directly affected by ischemia
anoxic core
oxygen deprivation
cells unable to meet metabolic needs
-depolarization of the membrane (Na+/K+ pump shuts down)
-causes APs to be released and NTs cause activation of receptors of whereever they synapse
high levels of EAA effect
EAA release is excessive, EAA re-uptake is Na+ dependent so not working
-NMDA receptor is activated = calcium influx
what does an increased in Ca++ initiate
activation of phospholipase A2
activation of calcineurin (phosphatase)
activation of mu-calpain (protease)
activation of apoptotic pathway
CAMP
excessive activation of phospholipase A2 effect
too much arachidonate acid release from membrane, causes physical damage
- arachidonate acts at ryanodine receptor on ER increases calcium even more
- unfolded protein response- stops making protein
- activation of eIF2a-kinase
- mitochondria impaired function
activation of u-caplpain (protease)
proteolysis: chews up existing proteins, damages neurons that weren’t hypoxic enough to die
- spectrin chewed up (structural damage)
- eIF4G chewed up (needed for protein synthesis)
activation of calcineurin
phosphatase
increases NO synthesis which becomes elevated to a toxic level
apoptotic pathway
disruption of mitochond and ER function increases free cytosolic calcium
-cytochrome C leaks, activates caspase 9 which activates caspase 3 (proteolytic enzyme, apoptotic)
reperfusion injury
when give blood and oxygen back to damaged area much of the O2 wil end up as a free radical bc damaged neurons no longer utilize oxygen correctly = radical
mitochondria that can make ATP in hypoxic cells
___ phosphorylation leads to apoptosis
make ATP, kinases take ATP and phosphorylate things that you do not want phosphorylated
-eIF2a kinase phosphorylation leads to decrease in protein syn and activates caspase 3 —>apoptosis
in high quantity NO contributes to edema by
damaging capillary endothelial cells
how do you treat excitotoxicity
try to stop NMDA receptors
-PCP?? i want some