EAA & Excitotoxity Flashcards
- Derived from α-ketoglutarate
* Metabolic and transmitter pool strictly separated.
Glutamate
• Often co-localized with glutamate
• Serves as neurotransmitter on its
own in visual cortex and
pyramidal cells.
• Metabolic and transmitter pool strictly separated.
Aspartate
EAA Location
Widely distributed throughout CNS
EAA receptors?
- Both ionotropic and metabotropic receptors
* Several kinds of each
Ionotropic Receptor:
The NMDA Receptor
• ? is an exogenous agent that activates these receptors.
- Glutamate, aspartate, etc… all activate them in the body.
- When activated, the channel allows influx of ?
• Has multiple modulatory sites
- ? binding site
- NMDA
- calcium
- GLYCINE
NMDA Receptor
• is a required co-agonist, but it alone cannot open the channel
• Both EAA and ? must be present for the channel to open.
GLYCINE binding site
- glycine
NMDA Receptor
• Within the channel itself
• Blocks the channel at resting membrane potential
Magnesium (Mg++) binding site
NMDA Receptor
- Prevents ? influx when the channel opens
- Makes the NMDA receptor both ligand- and voltage-gated.
Magnesium (Mg++) binding site
- calcium
The NMDA Receptor
• Horse tranquilizer
• Blocks channel
PCP binding site
2 main types of non-NMDA receptor
- AMPA
- Kainate
Also ionotropic – but primarily a Na influx
non-NMDA receptors
- Exogenous agent ? activated
- Glutamate/Aspartate are the endogenous ligands
- Modulatory sites as well.
- Sodium influx when open
AMPA
AMPA
- ? bind to a site on the extracellular face of the protein
- reduce the amount of sodium that enters
Benzodiazepines
? Receptors
- Sodium comes in and a little calcium as well
Kainate Receptors
Activation of the ? receptors produces a typical excitatory post- synaptic potential (epsp) with a relatively short onset and duration.
Non-NMDA
While activation of the ? receptors produces a “long” latency epsp with a long duration.
NMDA
Why does the epsp produced by activation of NMDA
receptors have a longer latency and longer duration than a
typical epsp?
- Blocked by magnesium and prevents calcium
- Get magnesium away from channel by depolarizing the cell
- So the delay is the time it took to get magnesium out of the way
- Takes long because its a calcium influx
Functions of Non-NMDA receptors
- Primary sensory afferents
- Upper motoneurons
- Too many to name
Functions of NMDA receptors
- Critical in short- and long-term memory formation
* Synaptic plasticity in many forms
Metabotropic Receptor
- 3 groups
1. Group 1: ? coupled
2. Group 2 & 3: ? coupled
- Gq
- Gi
Metabotropic Receptor
Functions
- Pre-synaptic:
-Post-synaptic:
• Pre-synaptic: control NT release • Post-synaptic: - Learning - Memory - Motor systems
Functions and where of NO?
• Memory
- Long-term potentiation
- In hippocampus & cerebellum
- Elsewhere
• Cardiovascular and respiratory control
- Pons and medulla
Downsides of NO
- Vary unstable – half-life is about 5 seconds.
- Leads to production of free radicals.
- In high concentrations – toxic to neurons
The uptake of the EAA is dependent on secondary active transport of ?
Na+
Excitotoxicity
• “Substantial evidence” for involvement in: ?
• “Strong evidence” for involvement in ?.
• “Substantial evidence” for involvement in:
- Strokes
- Global hypoxia or anoxia
- Traumatic injury to brain - Hypoglycemia
• epilepsy
What are the 4 consequences of high intracellular calcium?
- Increase in Phospholipase A
activity. - Activation of μ-calpain (a proteolytic enzyme)
- Activation of calcineurin
- Activation of the apoptotic pathway
Consequences of high intracellular calcium:
- Increase in Phospholipase A activity.
- Acts on membrane to release ?
- Physical damage to the membrane with high activation!!
- Arachidonic Acid
Consequences of high intracellular calcium:
- Increase in Phospholipase A activity.
• Arachidonic acid becomes another messenger and leads to:
- ? release from ER &
mitochondria - ? – ER stops
making proteins - ? activation
- ? dysfunction
- Ca++
- Unfolded protein
response *** - eIF2α-kinase
- Mitochondrial
Consequences of high intracellular calcium:
- Activation of μ-calpain (a proteolytic enzyme)
- Proteolysis of structural proteins, including ?.
- Proteoloysis of other enzymes, proteins,
including ? (further disruption of protein
synthesis). - Leads to ?
- spectrin
- eIF4G
- Leads to metabolic and
structural impairment of neurons. ***
Consequences of high intracellular calcium:
- Activation of calcineurin
• Excess production of ? via activation of ?.
- Nitric Oxide (NO)
- nitric oxide synthase (NOS)
Consequences of high intracellular calcium:
- Activation of the apoptotic pathway
• A consequence of the
previous steps, in particular the release of calcium from intracellular stores.
• Mitochondrial release of
enzymes, including ?
- Activation of ?
- ? is pro-apoptotic.
- caspase 9
- Caspase 3
- Caspase 3
Reperfusion
- What happens to oxygen?
Free Radicals
Reperfusion
- Kinases take ATP and convert it into?
- ADP and PO4
Reperfusion
- Phosphorylation of ? leads to a FURTHER decrease in protein synthesis & FURTHER activates ?, which FURTHER INCREASES ? signaling.
- eIF2α kinase
- caspase 3
- apoptotic
Acetylcholine
- Function and location?
Location
- Brainstem –> Arousal
- Basal Ganglia- Striatum –> motor control
Ionotropic Receptor
- NT : Acetylcholine
- Agonist: ?
- Modulator: X
- Ion: ?
- Agonist: Nicotine and Acetylcholine
- Ion: Na+ and a little calcium because the channel has 5 subunits
Metabotropic Receptors
- Agonists: ?
- G-protein coupled: ?
- General Effects: ?
- Agonists: Muscarine/Ach
- G-protein coupled: M1, 3, 5 coupled to a Gq protein (IP3 and diacylglycerol and calcium release)
- General Effects: M2 and 4 = connected to Gi (inhibitory- decreases adenylate cyclase)
