Excitotoxicity - Karius 3/23 Flashcards
Where is aspartate found?
Visual cortex and pyramidal cells
Often with glutamate
Is the NMDA receptor ionotropic or Metabotropic?
Ionotropic
What does the NMDA receptor allow for when activated?
What else is needed before substance can enter?
Ca2+
Glycine
What blocks the channel and prevents the influx of calcium?
When will this blockage end?
Mg2+
When the cell is depolarized
What additional binding site is internal to Mg2+ and will block the calcium channel?
PCP binding site
Describe the EPSP of the NMDA receptor in terms of onset and duration
Slow onset (Time to remove Mg)
Prolonged duration (Ca slower)
What are the types of non-NMDA receptors?
AMPA
Kainate
What enters the cell when AMPA receptors are activated?
What other site does it have and what does it do?
Na
Benzodiazepine site (inhibits response to nt)
When the kainate receptor is activated what enters the cell?
Na
Little Ca
Fx of non-NMDA receptors?
Primary afferents
Premotor (upper mn)
Fx of NMDA receptors?
Long-term changes in synaptic strength
Learning
Memory
Fx of Metabotropic receptors?
Learning
Memory
Motor systems
What gets rid of EAA?
Neurons and glia
Glia
How do the neurons get rid of EAA?
Na secondary active transport
High affinity for Glu and Asp only
How do the glia get rid of EAA?
Convert to glutamine (inactive form) and release it into the ECF
How is NO made in the presence of NMDA receptors?
NMDA receptor activated -> Ca2+ influx -> binds calcineurin -> activates NOS
NOS catalyzes Arg -> NO
Neural Fx of NO?
Long-term potentiation and memory
Cardiovascular and respiratory control
How can NO be toxic?
Leads to production of free radicals
Kill invading bacteria
What happens in the area most directly affected by ischemia?
Oxygen deprivation
Cells unable to meet metabolic needs and depolarization of membrane occurs
How does increased Ca influx affect the membrane?
Activation of PLA2 -> release of arachidonate from membrane causes physical damage to it
What else does Ca influx do to calcium stores?
Releases Ca from intracellular stores in the ER and mitochondria
Release of Ca from ER triggers what?
What does this do?
What does this activate?
Unfolded protein response
Stops making protein
eIF2a-kinase
What else does excess Calcium activate?
Mu-calpain (protease)
What does mu-calapin do?
Proteolysis of spectrin and eIF4G
Therefore metabolic impairment
How does increased calcium influx affect calcineurin?
Activates NOS and INC NO synthesis
Disruption of mitochondria and ER function causes what?
INC free cytosolic Ca thus leading to apoptosis
What to mitochondria release when dumping their calcium?
What do these activate?
Cytochrome C and Caspase 9
Caspase 3 -> apoptosis
What happens in a reperfusion injury?
Hypoxic neurons are not normal, oxygen will end up as a free radical
When reperfusion occurs, what do kinases do with ATP?
What happens?
ATP -> ADP + PO4
Phosphorylation of eIF2alpha kinase leads to a DEC in protein synthesis and activates Caspase 3
How can NO add to the cascade?
Causes edema by damaging capillary endothelial cells
What are the excitatory amino acids and what do they come from?
Glutamate from alpha-ketoglutarate
Aspartate from oxaloacetate
