glutamate Flashcards
what are synapses?
the areas where neurones make connections with each other, synaptic bouton synapses onto dendrites
-electrical signal is converted to a chemical signal and back to an electrical signal
what is glutamate?
major excitatory neurotransmitter in the CNS
-all excitatory neurons in the CNS are glutamatergic
what is glutamate synthesised from?
glutamine, converted to glutamate by phosphate-activate glutaminase
where is glutamate synthesised?
-synthesised in the nerve terminals
where is glutamate stored?
- packaged into vesicles by vesicular glutamate transporter (VGLUT)
- counter transported with H+ ions
- intracellular environment of vesicles is very acidic, so H+ ions diffuse out of the vesicle down their concentration gradient into the cytosol, glutamate enters
2 types of glutamate receptors?
- ionotropic
- metabotropic
types of ionotropic glutamate receptors?
AMPA receptors
NMDA receptors
Kainate receptors
-can be activated by glutamate or their respective agonists, eg. AMPA molecules etc.
What is the response when glutamate activates the different ionotropic receptors?
With AMPA and Kainate, we get the influx of Na+ and the efflux of K+
With NMDA, we get the influx of Na+ and Ca2+, and the efflux of K+
describe AMPA receptors
Four subunit types (plus alternate splice variants):
GluA1
GluA2
GluA3
GluA4
Hetero-tetrameric - Four orthosteric binding sites. Commonly 2 GluA2 subunits with
2 GluA1, 3 or 4
Presence of GluA2 subunits prevents Ca2+ flow - protective effect
Two sites must be occupied for channel opening.
Higher agonist concentration means more binding sites occupied, so greater ion flow through the receptor - current increases
describe NMDA receptors
Three subunit types:
GluN1 (or NR1)
GluN2 (or NR2)
GluN3 (or NR3)
Hetero-tetrameric
GluN3 subunits are inhibitory to NMDA receptor function, reducing excitotoxicity
All sites must be occupied for channel opening.
2 ligands – glutamate (GluN2) and glycine (GluN1) - can be occupied by glycine or serine. NMDA receptor requires both in order to be activated.
At rest, NDMA receptors have magnesium molecule blocking their channel
-depolarized neuron, magnesium exits, NMDA receptor enables ions to flow
function of GluN3 subunit in NMDA receptors
inhibitory to NMDA receptor function, becomes a non-functioning receptor
-reducing excitotoxicity
Glutamate synaptic plasticity
AP, glutamate release
-AMPA receptors activated first,
sodium flows into cell and, postsynaptic cell depolarises
-removes magnesium block, activating NMDA receptor
-sodium and calcium influx, further depolarisation of the cell
-calcium influx causes the cell to make and traffic more AMPA receptors to the post-synaptic membrane, means more current can pass, even larger depolarisation
-calcium activates CamKinase 2 enzyme, phosphorylates AMPA receptors, increasing their permeability and allowing them to pass more ions through per channel opening
If we were to measure the AP post synaptically, we would see LTP - changes aren’t readily reversible and they persist long term
what is LTP important for?
synaptic strengthening, and learning and memory
describe kainate receptors
Five subunit types:
GluR5 (GluK1) GluR6 (GluK2) GluR7 (GluK3) KA1 (GluK4) KA2 (GluK5)
Tetrameric:
GluK1-3 can form homomers or heteromers.
GluK4 & 5 only heteromers with GluK1-3 subunits.
Glutamate binding required for channel opening not well understood.
Metabotropic receptors
mGlu1-8 split into groups 1, 2 and 3 mGlu1 and 5 = group 1 mGlu2 and 3 = group 2 rest in group 3
Group 1 = Gq coupled
- PIP2 cleaved into DAG and IP3
- IP3 binds to receptors on ER, releasing Ca2+ from internal store into the cell
eg. causes CAM2 phosphorylation, leads to AMPA receptor activation
Group 2 and 3 receptors are coupled to the Gi/o proteins, inhibit AC, decrease cAMP formation
-reduce neurotransmitter release
