Excitatory Amino Acids and Excitotoxicity Lecture (Dr. Karius) Flashcards
Excitatory Amino Acids
1) Glutamate
2) Aspartate
**There are OHT Inotropic and Metabotropic Receptors that can be activated by EAA
Glutamate
- From ALPHA-KETOGLUTARATE
- Metabolic and NT pools Strictly SEPARATED!!!!!!
Aspartate
- From OXALOACETATE
- Documented as NT in Visual Cortex and Pyramidal Cells
- Often found with GLUTAMATE
Inotropic Receptors for EAA
1) NMDA
2) Non- NMDA Receptors
a) AMPA
b) Kainate
NMDA Receptors
- Activated by the Exogenous agent N-METHYL-D-ASPARTATE
- Also Glutamate and Aspartate
- When activated, allows CA++ INFLUX!!!!!!!!!!!!
- Has Multiple Modulatory Sites:
a) Glycine Binding Site
b) Mg++ Binding Site
c) PCP Binding Site - Activation leads to EPSP
a) SLOW ONSET
b) PROLONGED Duration
Glycine Binding Site on NMDA Receptors
- Glycine serves as a CO-AGONIST!!!!!!!
- Presence of Glycine required for EAA to have Effect
- Glycine on own CANNOT OPEN CHANNEL!!!!!
Magnesium Binding Site on NMDA Receptors
- INSIDE CHANNEL!!!!
- Mg++ blocks the Channel
a) CHANNEL MUST OPEN
b) Cell must be DEPOLARIZED for Mg++ to Leave
PCP Binding Site on NMDA Receptor
- INSIDE CHANNEL (Internal to Mg++ site)
- Blocks the Channel
Activation fo NMDA Receptors leads to EPSP’s in the POST-Synaptic Cell
The EPSP’s Show:
1) LONGER Latency (Time to remove Mg++)
2) Longer Duration (Ca++ Slower)
Non-NMDA Receptors
- Like the NMDA Receptor, almost exclusively POST-SYNAPTIC EXPRESSION
- SODIUM INFLUX (Some: Very small amount of Calcium too)
- Two Subtypes:
a) AMPA
b) KAINATE - Activation leads to TYPICAL EPSP
- Often Co-Localized at SAME SYNAPSE with NMDA Receptor!!!!!!!!!!
(The Non-NMDA Receptor allows for an Influx of Sodium which Depolarizes the Cell, thus removing the Mg++ Inhibition and therefore allowing and INFLUX of Ca++)
**BENZODIAZEPINE INHIBITS response to NT on the AMPA Non- NMDA Receptor!!!!!!!!
Metabotropic Receptors
- Both PRE and POST-SYNAPTIC Location
a) Pre-Synaptic: CONTROL Neurotransmitter Release!!!!!!
Functions of EAA
1) Non-NMDA Receptors:
- Primary AFFERENTS
- PREMOTOR (Upper MN)
2) NMDA Receptors:
- LONG TERM Changes in Synaptic Strength
- Learning
- Memory
3) METABOTROPIC Receptors:
- Learning
- Memory
- Motor Systems
Getting Rid of EAA
1) NEURONS and GLIA:
- Uptake Systems
a) Na+ Dependent Secondary Active Transport
b) High AFFINITY
2) GLIA:
- Convert to GLUTAMINE
- Release into ECF
***Neurons takes Glutamine up and convert it back to GLUTAMATE
EAA and Nitric Oxide
NMDA Receptors:
- Influx of Ca++
- Ca++ binds to CALCINEURIN!!!!!!!!!!!!!!
- Activates NITRIC OXIDE SYNTHASE (NOS)
- NOS catalyzes the reaction which creates NO from ARGININE!!!!!!
Neural Functions of NO
- Long term Potentiation and Memory
- Cardiovascular and Respiratory Control
Nitric Oxide can be Very Toxic
- Leads to production of FREE RADICALS
- These KILL invading Bacteria (or other cells)
EAA
Glutamate/ Aspartate/ Taurine
CENTRAL LOCATION:
- Widespread: Spinal Cord through to Cortex
FUNCTIONS:
- Sensory: Primary AFFERENTS
- Motor: Activation of Alpha Motoneuron
- Consciousness
- Learning
- Memory
IONOTROPIC RECEPTORS:
- NMDA: Ca++ Influx Modulatory Sites
- Non- NMDA: Sodium Influx; two Subtypes
METABOTRPIC RECEPTORS:
- Yes
OTHER:
- Creation of NO by NMDA Receptor Activation
Excitotoxicity
- Proposed to explain continuing Neuronal Deatha after and Ischemic Event
- Based on possibility that OVER STIMULATION of EAA System can cause CELL DEATH even in Neurons that were not ISCHEMIC/ HYPOXIC/ ANOXIC
Excitotoxicity
Strong evidence of Involvement in:
- Cerebral Ischemia/ Stroke
- Hypoxia or Anoxia
- Mechanical Trauma to CNS
- Hypoglycemia
Substantial evidence of Involvement in:
- EPILEPSY
In the area most Directly affected by Ischemia (Anoxic Core):
- OXYGEN DEPRIVATION
- Cells unable to MEET METABOLIC NEEDS (DEPOLARIZATION of MEMBRANE)
1) **Within 4 MINS:
- ATP levels within Neuron to 0
- Na/ K ATPase Ceases
- Vm DEPOLARIZES!!!!!!!
2) High levels of EAA:
- EAA release EXCESSIVE
- EAA Re-uptake is Na+ Dependent
3) NMDA Receptor Activation:
- CALCIUM INFLUX!!!!!!!!!!!!!!!!!
Increases Calcium Concentration initiates
1) Activation of Phospholipase A2
2) Activation of Calcineurin (Phosphatase)
3) Activation of Mu-Calpain (Protease)
4) Activation of Apoptotic Pathway
Excessive activation of these Enzymes disrupts Normal Cellular Function:
Activation of PHOSPHOLIPASE A2
- Release of Arachidonae from Membrane:
1) Causes PHYSICAL DAMAGE to MEMBRANE!!!!!
(Arachidonate acts as Ryanodine Receptor on ER)
2) RELEASE of CALCIUM from INTRACELLULAR STORES!!!!!!!!!!!!(Including E.R and Mitochondria)
3) ER:
- ‘UNFOLDED PROTEIN RESPONSE”: Stops making Protein
- Activation of eIF2Alpha-Kinase
- Mitochondria: Impaired Function
Excessive activation of these Enzymes disrupts Normal Cellular Function:
Activation of Mu-CALPAIN (Protease)
PROTEOLYSIS:
1) SPECTRIN: More structural Damage to Cell
2) eIF4G: Eukaryotic Induction factor 4G—> Protein Syntehsis
3) Others: Metabolic Impairment
Excessive activation of these Enzymes disrupts Normal Cellular Function:
Activation of CALCINEURIN
- **PHOSPHATASE:
- Among other things, ACTIVATES NOS
- INCREASES NO SYNTHESIS
Disruption of Mitochondrial and ER
A) The Disruption of Mitochondrial and ER Function INCREASES Free Cytosolic CALCIUM
B) As Mitochondrial Membranes are Disrupted, APOPTOTIC Pathways are ACTIVATED
- Cytochrome C and Caspase 9———————————————————–»» ACTIVATION of CASPASE 3 (Proteolytic Enzyme, Apoptotic)
Reperfusion Injury
- This Neuron is no longer “NORMAL”
- Much of this O2 being added will end up as a FREE RADICAL somewhere (PEROXIDES)
- Kinases take ATP —> ADP “ PO4
a) PHOSPHORYLATIO, further modifying Enzyme Action
b) PHOSPHORYLATION of eIF2alpha Kinase leads to a DECREASE in Protein Synthesis and activates CASPASE 3, which INCREASES APOPTOTIC Signaling
Nitric Oxide adds to the Cascade
- In HIGH QUANTITY, NO contributes to EDEMA by damaging Capillary Endothelial Cells!!!!
Prevention of this Cycle:
- Difficult at best, to date, most experimentally successful treatment are Pre-treatments that focus on NMDA Receptors
