Neurotransmitter Systems I: Glutamate Flashcards
what is the criteria for a neurotransmitter?
Neurotransmitters are chemical messengers that transmit signals from a neuron to a target cell across a synapse
1. The molecule must be synthesised and stored in the pre-synaptic neuron 2. The molecule must be released by the pre-synaptic axon terminal upon stimulation, triggered by the arrival of an action potential 3. The molecule must produce a response in the post-synaptic cell through the binding to post-synaptic receptors
how can neurons be classified based on neurotransmitters?
Neurons can be classified by the neurotransmitter that they use – these differences arise due to the differential expression of proteins involved in neurotransmitter synthesis, storage and release.
Neurons that communicate with glutamate are glutamatergic
What is glutamate?
Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS)
It is at the crossroad of multiple metabolic pathways
Nearly all excitatory neurons in the CNS are glutamatergic and it has been estimated that over half of all brain synapses release glutamate
How is glutamate synthesised and stored?
Glutamate can be synthesised form glucose but the main compound it is synthesised from is glutamine
Glutaminase, a phosphate activated enzyme, catalyses the conversion of glutamine to glutamate
It catalyses the conversion from an amine group to carboxylic acid group
It is synthesised in the nerve terminal
Once synthesised glutamate is transported into synaptic vesicles by vesicular glutamate transporters (VGLUT)
The inside of synaptic vesicles is very acidic as movement of hydrogen ions down the concentration gradient drives the entry of glutamate into vesicles
What happens during glutamate reuptake and degradation?
Reuptake:
Neurons and glial cells contain excitatory amino acid transporters EEATs which are a family of 5 different Na+ dependent glutamate co-transporters which function to transport glutamate from the synaptic cleft back into the neuron or glial cell for degradation
Degradation:
Glutamate transported into the glial cells via the EAATs is converted into glutamine via the action of glutamine synthetase
Glutamine is then transported out of the glial cells by a second transporter, termed the system N transporter (SN1) where it is then transported to neurons by system A transporter 2 (SAT2)
This overall sequence of events is termed the glutamate-glutamine cycle
What are the ionotropic glutamate receptors and the agonists that activate them?
Ionotropic glutamate receptors are named after agonists that activate them
AMPA- AMPA agonist, NA+ influx, K+ efflux
NMDA- NMDA agonist, Na+ and Ca2+ influx and K+ efflux
Kainate- Kainic acid, Na+ influx and K+ efflux
What are the AMPA receptors like?
Four subunit types (plus alternate splice variants):
- GluA1
- GluA2
- GluA3
- GluA4
Hetero-tetrameric structure
Four orthosteric binding sites
Two sites must be occupied for channel opening
Current increases as more binding sites are occupied
Most commonly:
2 GluA2 subunits
2 GluA1, 3 or 4
Presence of GluA2 subunits prevents Ca2+ flow, of substituted it becomes permeable to calcium
What are NMDA receptors like?
Three subunit types (plus alternate splice variants):
• GluN1 (or NR1)
• GluN2 (or NR2)
• GluN3 (or NR3)
• Hetero-tetrameric structure
• GluN3 subunits are inhibitory to NMDA receptor function
Ligand and voltage gated:
Ligands- glutamate and glycine or D-serine
All sites must be occupied for channel opening
Voltage gated so there is a Mg2+ block at resting membrane potential
What are kainate receptors like?
Five subunit types (plus alternate splice variants):
• GluK1 (GluR5)
• GluK2 (GluR6)
• GluK3 (GluR7)
• GluK4 (KA1)
• GluK5 (KA2)
Tetrameric:
GluK 1-3 can form homomers or heteromers
GluK1 and 5 only heteromers with GluK1-3 subunits
Ligand-gated ion channel:
• Glutamate binding required for channel opening – not particularly well understood
• Limited distribution in the brain compared to AMPA/NMDA receptors
What are the metabotropic glutamate receptors?
The metabotropic glutamate receptors comprise a large extracellular domain for neurotransmitter binding which can be termed as a Venus flytrap domain
A characteristic 7-transmembrane domain structure
And an intracellular C-terminal domain
In total there are 8 subtypes of metabotropic glutamate receptors mGlu1 through to 8
These can be placed into three distinct groups with each group possessing its own distinct properties
- Group 1- mGlu1 and 5
- Group 2- mGlu2 and 3
- Group 3- mGlu4, 6, 7 and 8
Form dimers that can be homomers, heteromers between different mGlu numbers and heteromers between mGlus and entirely different classes of receptor
How does each type of metabotropic glutamate receptor differ?
Group 1 receptors are coupled to Gq which is coupled to the pathway of IP3 which activates its own receptor leading to calcium release
- Used in synaptic plasticity and LTP
Group 2 and 3 are coupled to Gi/o which is coupled to a pathway involving the inhibition of adenylate cyclase which inhibits cAMP production
- Classified as auto-receptors as they have been shown to inhibit NT release
Group 1 are post synaptic while Group 2 and 3 are predominantly pre-synaptic
What effect does glutamate have on potential?
Excitatory neurotransmitters (e.g. glutamate) can lead to neuronal membrane depolarisation – displacement of a membrane potential towards a more positive value.
What are EPSCs, and how do they differ between receptors
The excitatory post-synaptic current (EPSC) represents the flow of ions, and change in current, across a post-synaptic membrane.
EPSCs lead to the generation of excitatory post synaptic potentials (EPSPs), which increase the likelihood of firing an action potential
EPSCs produced by the NMDA receptor and kainate receptor are slower and last longer than those produced by AMPA receptors
Accordingly, AMPA receptors are the primary mediators of excitatory neurotransmission in the brain
What happens during glutamate-mediated excitotoxicity?
Excitotoxicity is the pathological process by which excessive excitatory stimulation can lead to neuronal damage and death.
If there is too much of a build up of glutamate in the synaptic terminal EAATs begin to pump glutamate out of the terminal into the synaptic cleft even without the stimulus
This activation leads to an influx of Na+ and Ca+
Excessive Ca2+ can cause:
Mitochondrial damage
Oxidative stress
Apoptosis
Excitotoxicity linked to:
Stroke
Alzheimer’s
How does glutamate-mediated excitotoxicity in Alzheimer’s disease?
Neurodegenerative
NMDA receptor overactivation has been linked to neuronal cell death
A drug that targets NMDA receptors is one of the only treatments for Alheimers
Memantine is a low- affinity NMDA receptor antagonist that block the NMDA receptor ion channel to reduce glutamate mediated neurotoxicity
