Neurotransmitter systems I: Glutamate Flashcards
What is the major excitatory neurotransmitter?
glutamate
What is neurotransmission?
process that drives information between neurones and their targets (e.g. between neurone and another neurone or neurones and neuromuscular junction)
What are neurotransmitters?
chemical messengers that transmit signals from a neurone to a target cell across a synapse (e.g. neurotransmission)
What are the Requirements in order to be classed as a neurotransmitter?
a) Molecule must be synthesised and stored in presynaptic neurones
b) Molecule must be release by the presynaptic axon terminal upon stimulation by action potential (common mechanism in all neurotransmitters)
c) Molecule must produce a response via binding to a receptor in the post-synaptic cell
Describe the Initiation of action potential.
1) Resting membrane potential at -70mV.
2) Depolarisation- membrane potential becomes more positive due to the influx of Na+ ions after presence of stimulus
3) Rising phase of action potential- more and more Na+ channels open and more Na+ enters cell, reaching an action potential peak at about +30mV
4) Repolarisation- Na+ channels begin to close and K+ channels open, K+ efflux happens and membrane potential becomes more negative
5) Hyperpolarisation- membrane potential becomes more negative than resting potential due to the slow nature of K+ channels closing, before being restored to resting potential by Na+/K+ ATPase pump
Describe synaptic transmission.
1) Action potential arrive at synaptic bouton
2) Voltage gated calcium channels open and there is calcium influx
3) Increased intracellular calcium concentration initiates vesicle fusion with the presynaptic membrane
4) Neurotransmitter released by exocytosis across the synaptic cleft
5) Neurotransmitter binds to its complementary receptor
What are the major central neurotransmitters?
Acetylcholine Glutamate GABA Glycine Monoamines
Describe the process of Glutamate Synthesis.
Glutamine converted to glutamate in nerve terminals, which is catalysed by glutaminase, which is phosphate-activated
Describe how glutamate is stored.
transported into vesicles by vesicular glutamate transporters (VGLUT) via counter transport with H+:
-high H+ concentration in vesicles move along concentration gradient out of vesicles which is coupled with glutamate coming into vesicle
What are glutamate receptors?
Ionotropic Receptors:
· AMPA Receptors
· NMDA Receptors
· Kainate Receptors
Metabotropic Receptors:
· Group I
· Group II
· Group III
What are Ionotropic Glutamate Receptors?
Named after agonists that activate them:
a) AMPA receptors activated by a molecule called AMPA
b) NMDA receptors activated by a molecule called NMDA
c) Kainate receptors activated by a molecule called Kainic acid
Describe the structure of the Glutamate AMPA receptor.
4 subunit types:
- GluA1
- GluA2
- GluA3
- GluA4
hetero-tetrameric (“dimer of dimers”)
How many binding sites does the AMPA receptor have? How many must be occupied for channel opening?
Four orthosteric binding sites
Two sites must be occupied for channel opening
Current increases as more binding sites are occupied
What are AMPA receptors most commonly comprised of?
- 2 GluA2 subunits
- 2 GluA1/3/4 subunits
What do GluA2 subunits do?
prevent Ca2+ influx and can therefore be seen as protective against excitotoxicity
Describe the structure of the Glutamate NMDA Receptor.
3 subunit types:
- GluN1 (NR1)
- GluN2 (NR2)
- GluN3 (NR3)
hetero-tetrameric (“dimer of dimers”)
What are NMDA receptors mostly comprised of?
- 2 GluN1 subunits
- 2 GluN2/3 subunits
What do GluN3 subunits do?
inhibit NMDA receptor function
Give different Types of NMDA glutamate receptors.
Ligand and Voltage-gated NMDA receptors
Describe the Ligand NMDA glutamate receptor.
> Glycine or D-serine binds GluN1
>Glutamate binds GluN2
Describe the Voltage-gated NMDA glutamate receptor.
> Glycine or D-serine binds GluN1
Glutamate binds GluN2
Mg2+ block at resting membrane potential
during depolarisation event, Mg2+ will move out and allow ions to move freely
How many binding sites must be occupied for channel opening in NDMA receptors?
all binding sites must be occupied for channel opening
Define Synaptic Plasticity.
the ability of synapses to modify their strength
Describe the relationship between Glutamate and synaptic plasticity.
1) Glutamate released by pre-synaptic membrane
2) Glutamate binds post-synaptic AMPA receptors and there is Na+ influx via AMPA receptor channels causing depolarisation of post-synaptic membrane
3) Mg2+ block on NMDA receptors removed, allowing Ca2+ and Na+ influx via NMDA receptors channels
4) This can lead to receptor trafficking- new AMPA receptors can be made and inserted on the post-synaptic membrane
5) The extra AMPA receptors causes for more Na+ influx
6) Na+ influx then activates an enzyme called P-CamKinaseII which can phosphorylate and increase the ionic conductance of the receptors, meaning more Na+ and Ca2+ is entering the cell
7) This trafficking of receptors can underlie a process called Long-term Potentiation (LTP), which is a synaptic strengthening (due to the extra AMPA receptors inserted and extra ionic conductance, causing for stronger synapses)
8) This is an important process that underlies learning and memory
What do long term potentiations increase?
increase excitatory post-synaptic potentials (EPSPs)
Describe the structure of Glutamate Kainate Receptors.
5 subunit types:
- GluK1
- GluK2
- GluK3
- GluK4
- GluK5
tetrametic receptors:
- GluK1-3 can form homomers or heteromers
- GluK4&5 can only form heteromers with GluK1-3 subunits
What kind of receptors are glutamate kainate receptors?
ligand-gated ion channels:
- glutamate binding required for channel opening not well understood
- limited distribution in the brain
- function less well understood than AMPARs/NMDARs
What kind of receptor is a glutamate metabotropic receptor?
G-protein coupled receptors with:
a) Extracellular Venus Flytrap Domain: for ligand binding
b) 7 transmembrane Domains
c) Intracellular C-terminal Domain: coupled to G proteins
What are the types of Glutamate metabotropic receptors?
8 subtypes divided into 3 groups coupled to different G-proteins:
> Group 1 (Gq) (mGlu1, mGlu5)
- leads to an elevation in Ca2+
- important in long-term potentiation (LTP)/plasticity and transcription/translation
> Groups 2&3 (Gi/o) (mGlu2, mGlu3) (mGlu4,6,7,8)
- inhibiting adenylyl cyclase and decreasing cAMP
- inhibit neurotransmitter release
These receptors form dimers:
- Homomers
- Heteromers e.g. mGlu1 & mGlu5
- Heteromers e.g. mGlu2 & 5-HT2A
Where are group 1 glutamate metabotropic receptors located?
post-synaptically
Where are group 2&3 glutamate metabotrobic receptors located?
pre-synaptically
What are the Transporters which reuptake glutamate?
excitatory amino acid transporters (EAAT)
What is Excitotoxicity?
pathological process by which excessive excitatory stimulation (i.e. from an excitatory neurotransmitter such as glutamate) can lead to neuronal damage and death.
What causes excitotoxicity?
VGLUT transporters aren’t working
- no glutamate entering synaptic vesicles
- glutamate accumulates in the cytosol
- excitatory amino acid transporters (EAATs) reverse their function and transport glutamate into synaptic cleft
- glutamate bind AMPA receptors, causing Na+ influx, subsequently removing Mg2+ from NMDA receptors and binding NMDA receptors
- Ca2+ influx via NMDA receptors causing excessive Ca2+ in post-synaptic neurones
Why is excessive Ca2+ toxic?
Excessive Ca2+ can cause:
- mitochondrial damage
- oxidative stress
- apoptosis
What is excitotoxicity linked to?
Stroke
Autism
ALZHEIMER’s disease
Describe the Alzheimer’s brain.
- cerebral cortex shrinkage
- hippocampus (memory) shrinkage, hence memory loss
- severely enlarged ventricles
What is Alzheimer’s caused by?
Glutamate-mediated excitotoxicity
-excessive glutamate can lead to cell death, which can lead to shrinkage in the Alzheimer’s disease brain
What is Memantine?
NMDA receptor antagonist, blocking NMDA receptor channel to reduce glutamate mediated cytotoxicity by preventing excessive Ca2+ influx into post-synaptic membrane
