Glutamate Flashcards
What are the ionotropic glutamate receptors?
NMDA, AMPA, Kainate
What ions are NMDA receptors permeable to?
Sodium, Potassium, Calcium
How many subunits do all the ionotropic glutamate receptors have?
4 (Tetramers)
What is the subunit composition of an NMDA receptor?
Heterotetramer of…
Two GluN1 subunits
Two GluN2 subunits
Can also occasionally include GluN3
Agonists of the NMDA receptor
NMDA, Glutamate, Aspartate
Modulators of the NMDA receptor
Glycine, D-serine, Polyamines (such as magnesium and zinc)
Where can NMDA receptors be located?
Presynaptically
Postsynaptically
On glial cells
What responses is the NMDA receptor involved in?
Slower, longer-lasting EPSPs
Synaptic plasticity - LTP and LTD
Excitotoxicity
How many genes and splice forms are there for the GluN1 subunit?
1 gene
8 different splice forms
How many genes are there for the GluN2 subunit?
4 genes
Where on the NMDA receptor is the glycine binding site and what else can also bind here?
On the GluN1 subunit
Can bind glycine or D-serine
Where on the NMDA receptor is the glutamate (main) binding site?
On the GluN2 subunit
What are the 3 requirements for NMDA receptor activation?
Glutamate/Aspartate/NMDA binding
Co activation by glycine or D-serine
Depolarisation of neuron to remove the magnesium block
Where does the D-serine come from for co-activation?
Glial cells - this is how glial cells modulate neurotransmission
Examples of competitive antagonists of the NMDA receptor
AP5
CPPene
What ions are AMPA receptors permeable to?
Sodium and potassium, and SOMETIMES calcium
Where can AMPA receptors be located?
Postsynaptically
On glial cells
What are the functions of the AMPA receptor?
Mediates the majority of fast excitatory neurotransmission (Fast EPSPs)
What is the subunit composition of an AMPA receptor?
Made of up any 4 from GluA1-4 subunits
Always has GluA2 subunit
What determines whether or not an AMPA receptor is permeable to calcium?
The GluA2 subunit has a Q/R site in the amino acid chain in the pore-forming M2 region, that can be arginine or glutamine.
Glutamine = permeable
Arginine = impermeable
Name a competitive and a non-competitive antagonist of AMPA receptors
Competitive = NBQX
Non competitive = Telampanel
Name two positive allosteric modulators of the AMPA receptor
Cyclothiazide
Ampakines
What ions are Kainate receptors permeable to?
Sodium and potassium
What is the subunit composition of a Kainate receptor?
Made up of any 4 from GluK1-5 subunits
Where can Kainate receptors be located?
Presynaptically
Postsynaptically
(Limited distribution)
What are the functions of the Kainate receptor?
Fast EPSPs
Presynaptic inhibition
What is demoic acid?
Agonist of the kainate receptor
Found in mussels
Can cause seizures, motor weakness and death
Name two competitive antagonists of the kainate receptor
CNQX, ACET
What are the metabotropic glutamate receptors?
mGlu1-8
What are the groups of metabotropic glutamate receptors and which receptors does each group contain?
Group 1: mGlu 1, 5
Group 2: mGlu 2, 3
Group 3: mGlu 4, 6-8
What G-protein are Group 1 mGlu receptors coupled to?
Gq Activation of PLC PIP2 --> IP3 + DAG DAG activates PKC IP3 release calcium from ER
Where are Group 1 mGlu receptors located?
Postsyanptically
On glial cells
Where are Group 2 mGlu and group 3 mGlu receptors located?
Presynaptically
What G-protein are Group 2 and Group 3 mGlu receptors coupled to?
Gi/o
Inhibition of adenylyl cyclase
Less cAMP
Less PKA activation
What is the function of Group 1 mGlu receptors?
Slow excitatory neurotransmission
Increases postsynaptic intracellular calcium
What is the function of Group 2 and Group 3 mGlu receptors?
Slow inhibitory neurotransmission
Open presynaptic potassium channels
Reduce presynaptic intracellular calcium
Prevent neurotransmitter release
What charge does glutamate have?
Anion (negative charge)
Where does glutamate come from?
Non-essential amino acid (It is synthesised endogenously, you don’t need to eat it)
Which transporters move glutamate into neurons?
EAAT1-5 (mostly EAAT2)
Excitatory amino acid transporters
Which transporters move glutamate into vesicles?
VGLUT1-3
How is the action of glutamate terminated?
Diffusion and EAAT-mediated uptake
What are the features of a tripartite synapse?
Presynaptic neuron
Postsynaptic neuron
Astrocyte (or other glial cell)
How is glutamate in the synaptic cleft re-packaged into vesicles in the postsynaptic neuron?
Glutamate in the synaptic cleft transported into astrocytes by EAAT1/2
Glutamate broken down into glutamine by glutamine synthetase
Glutamine pumped back into extracellular space by Gln transporter
Glutamine uptaken by presynaptic cell byGln transporter
Glutamine converted into glutamate by glutaminase
Name two non-competitive, low affinity antagonists of NMDA receptors
Ketamine
Memantine
