Excitatory Amino Acids Flashcards
What extra molecule does glutamate have compared t aspartate ?
A methyl group
What are the 2 excitatory neurotransmitters in the brain ?
Glutamate (main one) and aspartate
Are glutamate and aspartate essential or non essential amino acids ?
Non essential because they can be made in the body
What is the abundance of glutamate and aspartate in the brain ?
Glutamate - 186mg/100g
Aspartate - 114mg/100g
What is pathway 1 for the synthesis of glutamate ?
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
What is pathway 2 in the synthesis of glutamate ?
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
What is the glutamine cycle ?
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
What 3 types of cells are present in the glutamine cycle ?
Presynaptic neuron
Postsynaptic neuron
Glial cell
What happens to glutamate after its release ?
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
How is glutamate broken down ?
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
How is glutamate stored into vesicles ?
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
How is glutamate released from the nerve terminal ?
Released by vesicular release however if the cytosol concentration is too high then it can be released by reversing the transporter
What is the transporter for glutamate like in the presynaptic membrane/glial cell ?
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
Facts about glutamate transporter subtypes
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
Where are each of the glutamate transporters found ?
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
What are the receptors of glutamate like?
Metabotropic - mGluR1-8 - slow and modulatory
Ionotropic - kainate, AMPA and NMDA - fast transmission
What are the class 1 metabotropic receptors and what do they do ?
mGluR 1 and 5
Linked to phospholipase c and increase IP3 causing release of calcium from intracellular stores
What are the class 2 metabotropic glutamate receptor and what effect do they have ?
mGluR 2 and 3
Decrease levels of cAMP
What are the class 3 metabotropic glutamate receptors and what effect do they have ?
mGluR 4, 6, 7 and 8
Autoreceptors
What activates class 1 and 2 metabotropic glutamate receptors ?
Trans-ACPD and quisqualate
What activates class 3 metabotropic glutamate receptors ?
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
What are agonists, antagonists, channel blockers, modulators and co agonists of NMDA receptors ?
Agonists- glutamate and aspartate Antagonists- APV Channel blockers - ketamine, magnesium, PCP and MK801 Modulators - magnesium and polyamines Coagonist- glycine
What are agonists and antagonists of AMPA and kainate receptors?
Agonists - glutamate and quisqualate
Antagonist - CNQX
What effect does polyamine have on NMDA receptors ?
Binds to its modulatory site and prevents activation of the channel
What happens when glycine and NMDA bind to NMDA receptors ?
If only one of these molecules binds then there is no effect
Response occurs when both bind
What happens when glutamate and glycine bind to NMDA receptors ?
When just glutamate binds it causes a slight depolarisation but when both glutamate and glycine bind the effect is much larger
Explain long term potentiation
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
What is long term potentiation involved in ?
Involved in memory formation an learning
It changes the plasticity of the synapse
How does LTP cause synaptic plasticity ?
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
What happens in neurotoxic cell death ?
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
What is epilepsy.?
Overstimulation of the glutamatergic system
What is riluzole used in and why ?
Used to slow decline of als by increasing glutamate uptake
What happen to glutamatergic system in ischaemia ?
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
