EAA and Excitoxicity Flashcards
Where does aspartate serve as a neurotransmitter?
visual cortex and pyramidal cells
What are the receptor types for EAA?
ionotropic and metabotropic
several kinds of each
What is the NMDA receptor?
EAAs activate it –> influx of calcium
has multiple modulatory sites - glycine binding site
How does glycine affect the NMDA receptor?
required co-agonist, but it alone cannot open the channel
both EAA and glycine must be present for the channel to open
How does magnesium affect the NMDA receptor?
within the channel itself
blocks the channel at resting membrane potential
prevents Ca influx when the channel opens
makes the receptor both ligand and voltage-gated
How does PCP affect the NMDA receptor?
blocks channel
What are the 2 main types of non-NMDA receptors for EAA?
AMPA
Kainate
What is AMPA?
non-NMDA receptor for EAA
ionotropic - primarily Na influx
glutamate/aspartate are the endogenous ligands
What is the main regulatory site for AMPA?
benzodiazepines bind site on extracellular face of protein
reduce the amt of sodium that enters
What is the difference in excitation from activation of non-NMDA and NMDA receptors?
non-NMDA: typical excitatory post-synaptic potential (epsp)
NMDA: long latency epsp w/ long duration
Why does NMDA receptor have a longer latency epsp?
non-nmda receptor act –> typical epsp –> depolarization can cause Mg to leave NMDA channel –> Ca now enters NMDA channel –> longer lasting epsp
What is the relationship based on location of non-NMDA and NMDA receptors?
non-NMDA receptors do not exist on post-synaptic membranes w/out NMDA receptors
in some systems
What are the functions of EAA receptors?
non-nmda: primary sensory afferents, upper motoneurons, others
nmda: critical in short and long-term memory formation, synaptic plasticity
What are the main groups of metabotropic EAA receptors and what is their GPCR type?
group 1: Gq
Groups 2 and 3: Gi
Where are EAA metabotropic receptors and what do they function in?
pre-synaptic: control NT release
post-synaptic: learning, memory, motor systems
How are EAAs broken down and how does this limit EAA actions?
glial cells surrounding synapses absorb EAA –> breakdown to glutamine = inactive
glutamine uptaken to presyn neuron and recycled to EAA
How are NMDA receptors and nitric oxide related?
EAA binds NMDA –> Ca influx –> binds calcineurin
NOS triggered to convert Arginine to NO
Influx of what ion is likely to cause an inhibitory post-syn potential (ipsp)?
chloride
What type of NT is glycine typically?
inhibitory
What is the main effect of EAA at NMDA receptors?
producing long-term changes in synaptic strength via a process known as long term potentiation
memory
learning
Which receptor is thought to be used with EAA for synaptic plasticity assoc w/ learning?
metabotropic receptors
What are the general effects of NO outside CNS?
increases cGMP in endothelial cells –> causes sm m relaxation
major inhibitory NT in gut –> relaxation
immune: free radial in macrophages to kill bacteria
What are the CNS effects of NO?
long term potentiation of presyn neuron (respiratory control, cardio control, memory/learning)
*major control of cerebral vasculature –> dilation
How is NO removed from a synapse?
no uptake system for NO as it is lipid soluble
half-life of 5 seconds and then it degrades
some proteins do bind it
What occurs to neuronal cells right after ischemia?
rapid reduction in ATP –> cell depolarizes as membrane ATPases stop working –> presyn cells release NTs –> excess activation of NMDA and non-NMDA receptors
How is the excess activation of EAA receptors further promoted during ischemia?
reuptake of EAA is dependent on Na concetration gradient
w/ energy depletion, gradient for Na degrades –> no reuptake –> a ton in the synapse
What happens to cells after ischemia causes excess EAA activation?
calcium enters cells –> voltage gated Ca channels open too
activation of phopholipase A and C, Calcineurin, and mu-calpain
What does the activation of phopholipases following an ischemic event cause?
act on cell membrane to release arachidonate from membrane –> physical damage
arachidonate –> ER and Mitochondria release calcium –> ER shows ulfolded protein response and ER kinases are activated
What does is mu-calpain?
a protease activated in ischemia –> damages structural and functional proteins within the cell
inhibits protein synthesis
What does release of calcium from the ER do to mitochondria?
mito membrane is disrupted –> cytochrome c and caspase 9 released –> caspase 3 –> apoptosis
What does oxygen do to damaged neurons during reperfusion?
taken into cells –> mitochondria make ATP
leftover O2 made into peroxide radicals –> peroxidation of lipids and membrane damage
elF2alpha kinase Piates elF2alpha –> inhibts protein synthesis and activates caspase 3 and CHOP –> apoptosis
How does epinephrine from ischemic injury damage cells?
able to get to tissue after reperfusion –> Beta receptors –> cAMP –> increased extracellular K and activates PKA –> more protein syn inhibition
What does ischemia do to endothelial cells lining blood vessels?
causes them to express cell adhesion molecules so WBCs can enter –> macrophages –> release NO and Histamine
How are ischemia and growth factors related?
ischemia impairs cells’ ability to respond to GFs bc of:
membrane damage
altered fxn of sendary messenger sys
inhibition of protein synthesis
What does increased blood flow during reperfusion do to the brain?
increase of vascular permeability bc of a ton of NO –> influx of fluid in damaged areas –> edema –> increased ICP –> compromizes blood flow to areas
What enzyme is directly responsible for structural damage to neurons during excitotoxicity?
mu-calpain
