Both ionotropic and metabotropic receptors Several kinds of each

NMDA Receptor Prevents ? influx when the channel opens Makes the NMDA receptor both ligand- and voltage-gated.

Magnesium (Mg++) binding site - calcium

EAA & Excitotoxity Flashcards by Kristina Assaf

Derived from α-ketoglutarate

* Metabolic and transmitter pool strictly separated.

Glutamate

How well did you know this?

Not at all

Perfectly

• Often co-localized with glutamate

• Serves as neurotransmitter on its
own in visual cortex and
pyramidal cells.

• Metabolic and transmitter pool strictly separated.

Aspartate

How well did you know this?

Not at all

Perfectly

EAA Location

Widely distributed throughout CNS

How well did you know this?

Not at all

Perfectly

EAA receptors?

Both ionotropic and metabotropic receptors

* Several kinds of each

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

NMDA Receptor
• Within the channel itself
• Blocks the channel at resting membrane potential

Magnesium (Mg++) binding site

How well did you know this?

Not at all

Perfectly

NMDA Receptor

Prevents ? influx when the channel opens
Makes the NMDA receptor both ligand- and voltage-gated.

Magnesium (Mg++) binding site

calcium

How well did you know this?

Not at all

Perfectly

The NMDA Receptor
• Horse tranquilizer
• Blocks channel

PCP binding site

How well did you know this?

Not at all

Perfectly

2 main types of non-NMDA receptor

AMPA

- Kainate

How well did you know this?

Not at all

Perfectly

Also ionotropic – but primarily a Na influx

non-NMDA receptors

How well did you know this?

Not at all

Perfectly

Exogenous agent ? activated
Glutamate/Aspartate are the endogenous ligands
Modulatory sites as well.
Sodium influx when open

AMPA

How well did you know this?

Not at all

Perfectly

AMPA

? bind to a site on the extracellular face of the protein
reduce the amount of sodium that enters

Benzodiazepines

How well did you know this?

Not at all

Perfectly

? Receptors

- Sodium comes in and a little calcium as well

Kainate Receptors

How well did you know this?

Not at all

Perfectly

Activation of the ? receptors produces a typical excitatory post- synaptic potential (epsp) with a relatively short onset and duration.

Non-NMDA

How well did you know this?

Not at all

Perfectly

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

- 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?

1. Increase in Phospholipase A activity. 2. Activation of μ-calpain (a proteolytic enzyme) 3. Activation of calcineurin 4. Activation of the apoptotic pathway

Consequences of high intracellular calcium: 1. 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: 1. 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: 2. 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: 3. Activation of calcineurin • Excess production of ? via activation of ?.

- Nitric Oxide (NO) | - nitric oxide synthase (NOS)

Consequences of high intracellular calcium: 4. 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)