Glutamate Flashcards
The main _ transmitter in the CNS
Excitatory
Glutamate is synthesised from…
Glutamine
Reuptake of glutamate is done by …
Excitatory Amino Acid Transporters (EAAT)
Synthesis of Glutamate
Glutamine transported into pre-synaptic neuron
Converted into glutamate
Stored in vesicles
Use and reuptake of Glutamate
During depolarization, vesicles bind to cell wall and release glutamate into synapse
Taken up again by EAAT
Stored in pre-synaptic neuron or in glial cell
Glutamine is transported into pre-synaptic neuron by …
Glutamine transporter
Glutamine is converted to glutamate by…
Glutaminase
What happens to synaptic glutamate?
Can be taken up by EAAT and stored back in the pre-synaptic neuron.
Can be taken up into the glial cell and stored as glutamine
Excitotoxicity
When there is so much excitation of glutamate receptors that it causes cell death.
Glutamate acts via _tropic and _tropic receptors
Ionotropic: NMDA, AMPA and KA
Metabotropic: Group I, Group II, Group III
NMDA receptor names
GluN1
GluN2A
etc
AMPA receptor names
GluA1
GluA2
etc
KA receptor names
GluK1
GluK2
etc
Group 1 receptors
mGluR1 and mGluR5
Increase calcium and IP3
Group 2 receptors
mGluR2 and mGluR3
Decrease cAMP
Group 3 Receptors
mGluR4, mGluR6, mGluR7, mGluR8
Decrease cAMP
Why can glutamate bind so many receptors?
Because it doesn’t have a rigid shape
Shape of glutamate
Nine ‘rotamers’ are possible
Contains different constituents that can rotate along two different axes about the alpha beta and beta gamma bonds
Structure of ionotropic glutamate receptors
Tetrameric ligand gated ion channels
Subunits have 4 membrane sections
Extracellular loop between 3 and 4 forms part of the binding principle
P-elements face inward and form the channel
Subunits of ionotropic glutamate receptors
1, 3 and 4 are trans-membrane segments
2 does not span the membrane (p-element)
Subunit composition can be heteromeric or homomeric
NDMA will never be…
homomeric
AMPAr receptor
Ligand gated Na+ channel
Permeable to Na+ in and K+ out
Ca2+ permeable if there is no GluA2 subunit
Fast excitatory transmission
Agonists of AMPAr receptors
Glutamate
AMPA
KA
Antagonists of AMPAr receptors
NBQX (competitive
GYKI 53655 (non-competitive)
NMDA receptor
Dual gated Na+/Ca2+ channel
Na+ out, K+ out, Ca2+ in
Voltage and ligand gated, depolarisation required to relieve Mg block
requires glycine or serine as co-agonist
Much slower time course than AMPA
Structure of NMDA receptor
1 GluN1 subunit and 3 GluN2A-D subunits
Glycine _ NMDA receptor mediated responses
potentiates
Competitive NMDA receptor antagonists
AP5 and CPP
NMDA receptor ion channel blockers
Ketamine (high affinity)
Memantine (low affinity)
PCP (dissociative anaesthetic)
mGluRs
GCPRs
7 transmembrane regions
Slow neuromodulatory role
Connected to different second messenger systems
mGluRs and Ca2+
Channels normally let Ca2+ in
Glutamate activates
Ca channel closure
Controls transmitter release
Activation of intracellular enzyme releases Ca2+ from intracellular stores
Activation of intracellular enzyme releases Ca2+ from intracellular stores
IP3
Initiation of second messenger cascade causes further enzyme activation.
Opening/closing of ion channels
Modulation of postsynaptic excitability
Important for excitotoxicity and neurodegeneration
mGluRs and K+
Channels normally let K+ out
Glutamate activates mGluR
Leads to K-channel closure
Leads to slow depolarization
mGluR1 and mGluR5
postsynaptic
produce slow depolarisation
release Ca2+ from intracellular stores
mGluR2, 3, 4, 7 & 8
presynaptic
usually inhibit glutamate (and other transmitters) release
Presynaptic NMDAr _ glutamate release by _ Ca influx.
increase, increase
Presynaptic mGluR _ glutamate release by _ Ca influx
decrease, decreasing
