Glutamate Flashcards
What occurs at synapses?
→ Synaptic transmission
→ Electrical → chemical → electrical
What are the 3 criteria for being a neurotransmitter?
→must be synthesized and stored in the presynaptic neuron - for fast transmission
→ be released by the presynaptic axon terminal upon stimulation
→ produce a response in the postsynaptic cells
How do vesicles fuse to the membrane?
→ Change in voltage when AP occurs
→ Activates voltage gated Ca2+ channels
→ Calcium rushes into the cell
→ Activates the proteins on the vesicles
→ Signals to fuse to the synaptic membrane
Describe action potential propagation
1) At rest the voltage gated K+ and Na+ channels are closed
2) There is a depolarising stimulus
3) this activates the voltage gated Na+ channels in the membrane
4) further Na+ influx and more depolarisation
5) At the top of the peak (~ +40mv) the Na+ channels are deactivated by plugging
6) No further influx of Na+ into the cell
7) The voltage gated K+ channels are activated and opened
8) K+ flows out of the membrane down its gradient
9) Voltage decreases
10) K+ channels are open for a bit too long so it hyperpolarises
11) Na+/K+ pump restores the resting potential
Why can the action potential only travel one way?
→ The sodium channels are plugged
→ Na+ can only move forwards
What are the 4 main neurotransmitters?
→ ACh
→ Glutamate
→ GABA
→ Glycine
What are amino acid neurotransmitters?
→ GABA
→ glutamate
→ glycine
Why are amino acid neurotransmitters called that?
→ their precursors are amino acids
How is glutamine turned into glutamate?
→ phosphate activated glutaminase
→ Amine group gets substituted by an oxygen
Where is glutamate synthesized?
→ In the nerve terminals
Describe how glutamate gets packaged into vesiscles
1) Glutamate is packed in the vesicles by vesicular glutamate transporter
2) It is counter transported with H+ ions
3) The intracellular environment of vesicles is very acidic so the H+ want to diffuse down their gradient
4) the transporter moves H+ out and glutamate in
Where is the AMPA receptor found?
→ Post synaptically
What are the 3 ionotropic receptors for glutamate?
→ AMPA
→ NMDA
→ Kainate
Why do the ionotropic receptors for glutamate have those names?
→ They all have the endogenous agonist glutamate
→ They can be activated by exogenous compounds
What are the 4 subunit types of AMPA receptors?
→ GluA1
→ GluA2
→ GluA3
→GluA4
What are the AMPA receptors composed of and what kind of receptor are they?
→ two GluA2 subunits
→ and two GluA1, 3 or 4
→ hetero-tetrameric
How many binding sites does the AMPA receptor have and how many must be occupied for channel opening?
→ 4 orthosteric binding sites
→ Two sites must be occupied for channel opening
What happens to an AMPA receptor as more binding sites are occupied?
→ Current increases
What protects against excitotoxicity in AMPA receptors?
→ Presence of GluA2 subunits prevent Ca2+ flow
What are the 3 subunit types of NMDA receptors?
→ GluN1
→ GluN2
→ GluN3
What are NMDA receptors composed of and what kind of a receptor are they?
→ two GluN1 subunits
→ two GluN2 or GluN3
→ heterotetrameric
What are the ligands for an NMDA receptor?
→ Glutamate
→ glycine
→ D-serine
How do GluN3 subunits affect NMDA?
→ they are inhibitory
What ion is important in synaptic plasticity?
→ Mg2+ block
→ Depolarisation leads to Mg exiting the channel allowing for influx of ions
Describe the process of synaptic plasticity
1) action potential
2) causes a graded potential of a certain size
3) The neurotransmitter binds to the AMPA receptors
4) it depolarises the synaptic cell
5) causes the Mg2+ block to leave the NMDA receptors
6) activates NMDA which further depolarises the cell
7) influx of Na+ and Ca2+
8) Ca2+ influx causes the cell to make and traffic more AMPA receptors to the membrane
9) There is an even larger depolarisation
10) Ca2+ activates CAM kinase II which phosphorylates AMPA receptors
11) allows AMPA to pass more current per channel opening and increases the permeability of AMPA receptors
12) The changes in membrane persist for a number of hours and days
What are the 5 subunits of kainate receptors?
→ GluR5
→ GluR6b
→ GluR7
→ KA1
→ KA2
→ Limited distribution in the brain compared to AMPA/NMDA receptors
What is excitotoxicity and what happens as a result of this?
→ too much excitation
→ damage to functioning of vesicular glutamate transporters
→ lots of glutamate in the cytosol → no gradient for transporters → glutamate is pumped out of the cell → released into cleft without stimulus → activation of AMPA and NMDA
What are the effects of excitotoxicity?
→ mitochondrial damage
→ Oxidative stress
→ Apoptosis
→ Stroke
→ Autism & Alzheimers
What type of receptors are metabotropic?
→ G couples receptors
How many types of metabotropic receptor are there for glutamate?
→ 8 types
What are the 3 subtypes of metabotropic glutamate receptor?
→ 1 - MGlu1 and MGlu5
→ 2- MGlu2 and Mglu 3
→ 3 - MGlu 4, MGlu 6, MGlu 7, MGlu 8
What type of G protein receptor are the group 1 subtype receptors?
→ Gq→ PIP2 → DAG and IP3
IP3R activation on ER
↑Ca2+
What type of G protein receptor are the group 2 and 3 subtype receptors?
→ Gi
→ block adenylyl cyclase→ reduced cMAP formation
→ autoreceptors
Where are the group 1 G protein subtype receptors found?
→ post synaptically
Where are the group 2 and 3 G protein subtype receptors found?
→ Presynaptically
What kind of a neurotransmitter is glutamate?
→ Excitatory
What are the domains that make up a G protein?
→ Venus flytrap domain
→ 7 transmembrane domain
→cysteine rich domain
→ C terminus domain
How can excitotoxicity be stopped?
→ memantine
→ a low affinity NMDA receptor
What enzyme is responsible for converting glutamine to glutamate?
→ Glutaminase- phosphate-activated
→ amine is substituted for carboxylic group.
How is glutamate re-uptaken into presynaptic neurones?
→ neurones and glial cells have excitatory amino acid transporters(EAAT)
→ sodium ion dependent
→ transports glutamate from cleft
How is glutamate degraded?
→ by glutamine synthetase
How is glutamine transported to neurones from glial cells?
→ SN1 = System N transporter (expressed on glial cells)
→ SAT2 = System A transporter 2 (expressed on neurons)
Which ionotropic glutamate receptor allows entry of Ca and Na?
→ NMDA
What is EPSC?
→ excitatory post-synaptic current (EPSC) represents the flow of ions, and change in current, across a post-synaptic membrane
What can EPSCs lead to?
excitatory post synaptic potentials (EPSPs)
Compare the EPSCs produced by NMDA and kainate receptors to AMPA receptors
NMDA receptor and kainate receptor are slower and last longer than those produced by AMPA receptors
Which ionotropic receptors are the primary mediators of excitatory neurotransmission?
→ AMPA
What is LTP?
→Long term potentiation
→ the persistent strengthening of a synapse based upon repeated patterns of activity.
→underlies important processes, including both learning and memory
Describe the mechanism for LTP
→ Glutamate activates AMPA receptors, with Na+ flowing into the post-synaptic neuron and causing depolarisation
→ NMDA receptors open, due to depolarisation removing the voltage-gated Mg2+ ion block
→ Ca2+ ions enter the cell activate post-synaptic protein kinases such as calmodulin kinase II (CaMKII) and protein kinase C (PKC)
→ CaMKII and PKC trigger a series of reactions that lead to the insertion of new AMPA receptors into the post-synaptic membrane
→ AMPA receptors increase the post-synaptic membranes sensitivity to glutamate and increases ion channel conductance
