Excitatory Amino Acids

Question 0

What extra molecule does glutamate have compared t aspartate ?

Answer 0

A methyl group

Question 1

What are the 2 excitatory neurotransmitters in the brain ?

Answer 1

Glutamate (main one) and aspartate

Question 2

Are glutamate and aspartate essential or non essential amino acids ?

Answer 2

Non essential because they can be made in the body

Question 3

What is the abundance of glutamate and aspartate in the brain ?

Answer 3

Glutamate - 186mg/100g

Aspartate - 114mg/100g

Question 4

What is pathway 1 for the synthesis of glutamate ?

Answer 4

It is made by glycolysis, the oxidative metabolism of glucose
Glucose to pyruvate to acetyl CoA which enters Krebs cycle and is converted to alpha- ketoglutarate to glutamate
The final step is known as transmigration by amino transferase

Question 5

What is pathway 2 in the synthesis of glutamate ?

Answer 5

Glutamine is converted to glutamate by glutaminase
Preferred pathway
Glutaminase undergoes product inhibition so once enough glutamate has been produced it creates a negative feedback loop preventing more being made

Question 6

What is the glutamine cycle ?

Answer 6

Glutamine is converted to glutamate by glutaminase - this is mostly present in nerve terminal
Glutamate is converted to glutamine by glutaminase synthetase - mostly in astrocytes

Question 7

What 3 types of cells are present in the glutamine cycle ?

Answer 7

Presynaptic neuron
Postsynaptic neuron
Glial cell

Question 8

What happens to glutamate after its release ?

Answer 8

It is taken up by glutamate transporters back into presynaptic nerve or more preferentially by glutamate transporter into glial cell
In glial cell it is converted to glutamine and then released to be taken up. by presynaptic nerve

Question 9

How is glutamate broken down ?

Answer 9

1- glutamate synthetase = breaks down glutamate into glutamine - mainly occurs in glia
2- reversal of transaminase reaction = break down glutamate into alpha- ketoglutarate -occurs in mitochondria
3- glutamate dehydrogenase = glut,ate broken down to alpha- ketoglutarate in mitochondria - used to re manufacture glutamate

Question 10

How is glutamate stored into vesicles ?

Answer 10

By VGLUT1-3 transporter - low affinity tranpsorter (1-2mM) because there is such as high concentration of glutamate in the cytosol.
Dependent upon proton anti porter system
- ATP is converted to ADP causing protons to enter the vesicle
- the VGLUT is then able to exchange the proton for a glutamate molecule

Question 11

How is glutamate released from the nerve terminal ?

Answer 11

Released by vesicular release however if the cytosol concentration is too high then it can be released by reversing the transporter

Question 12

What is the transporter for glutamate like in the presynaptic membrane/glial cell ?

Answer 12

It has a high affinity for glutamate - 10-40micromolar because the concentration of glutamate isn’t as high in the synaptic cleft
Low specificity - L-Glu, L and D asp, cysteate - these were originally describes as being of 3 types - neuronal, cerebellar and astrocytic but now it been discoverd there are at least 5
EEAT1-5

Question 13

Facts about glutamate transporter subtypes

Answer 13

525-573 amino acids n
55% homology
6-10 transmembrane domains
Important in disease States - abnormalities of these have been shown in als - increased levels of glutamate cause degeneration of neurons

Question 14

Where are each of the glutamate transporters found ?

Answer 14

1- neurons and glia- in Bergman glia, cortex, hippocampus and cerebellum
2- astroglia-
3- neurons
4- cerebellar purkinje in rat and human CNS
5- primarily in reTina

Question 15

What are the receptors of glutamate like?

Answer 15

Metabotropic - mGluR1-8 - slow and modulatory

Ionotropic - kainate, AMPA and NMDA - fast transmission

Question 16

What are the class 1 metabotropic receptors and what do they do ?

Answer 16

mGluR 1 and 5

Linked to phospholipase c and increase IP3 causing release of calcium from intracellular stores

Question 17

What are the class 2 metabotropic glutamate receptor and what effect do they have ?

Answer 17

mGluR 2 and 3

Decrease levels of cAMP

Question 18

What are the class 3 metabotropic glutamate receptors and what effect do they have ?

Answer 18

mGluR 4, 6, 7 and 8

Autoreceptors

Question 19

What activates class 1 and 2 metabotropic glutamate receptors ?

Answer 19

Trans-ACPD and quisqualate

Question 20

What activates class 3 metabotropic glutamate receptors ?

Answer 20

Not affected by trans-ACPD or quisqualate
Activated by L-AP4 and L-SOP
They also inhibit adenylate Cyclase so the different drugs which activate it makes it distinguishable from the class 2 receptors

Question 21

What are agonists, antagonists, channel blockers, modulators and co agonists of NMDA receptors ?

Answer 21

Agonists- glutamate and aspartate 
Antagonists- APV 
Channel blockers - ketamine, magnesium, PCP and MK801 
Modulators - magnesium and polyamines
Coagonist- glycine

Question 22

What are agonists and antagonists of AMPA and kainate receptors?

Answer 22

Agonists - glutamate and quisqualate

Antagonist - CNQX

Question 23

What effect does polyamine have on NMDA receptors ?

Answer 23

Binds to its modulatory site and prevents activation of the channel

Question 24

What happens when glycine and NMDA bind to NMDA receptors ?

Answer 24

If only one of these molecules binds then there is no effect
Response occurs when both bind

Question 25

What happens when glutamate and glycine bind to NMDA receptors ?

Answer 25

When just glutamate binds it causes a slight depolarisation but when both glutamate and glycine bind the effect is much larger

Question 26

Explain long term potentiation

Answer 26

If you repeatedly stimulate the preferent pathway of the ca1 region of the hippocampus then you will repeatedly see EPSPs in the postsynaptic neuron
If you then strongly excite the preferent pathway (100Hz for 1-2secs) this causes a conditioning train
Immediately after this conditioning train you see an increase in the size of EPSP

It fades away after a while but remains at a higher amplitude for a while
Therefore the strength of the synapse has changed so it is believed to be the first steps in forming memory

Question 27

What is long term potentiation involved in ?

Answer 27

Involved in memory formation an learning

It changes the plasticity of the synapse

Question 28

How does LTP cause synaptic plasticity ?

Answer 28

The conditioning train causes sustained depolarisation so it will cause the magnesium block of NMDA receptors to be removed
This allows sodium and calcium ions through
Increase in calcium increases protein kinase c

Metabotropic receptors will also be activated and this increases intracellular calcium ions
Causes a signalling cascad in the postsynaptic neuron which causes phosphorylation of AMPA receptors increasing their activity , causes changes in gene expression and changes in the synapse such as structural changes and he number of receptors

Question 29

What happens in neurotoxic cell death ?

Answer 29

When there is a calcium overload
Prevents sodium/potassium ATPase working properly which causes depolarisation of the cell
Causes unblocking of NMDA receptors so calcium enters
This can cause strokes

Question 30

What is epilepsy.?

Answer 30

Overstimulation of the glutamatergic system

Question 31

What is riluzole used in and why ?

Answer 31

Used to slow decline of als by increasing glutamate uptake

Question 32

What happen to glutamatergic system in ischaemia ?

Answer 32

Causes cell depolarisation
Causes glutamate release
Increases intracellular calcium
Causing the release of professes and other intracellular enzymes which can lead to damage of neurons and glia