Gluatamate Flashcards
What is neurotransmission?
The fundamental process that drives information transfer between neurons and their targets
What are neurotransmitters?
Chemical messengers that transmit signals from a neuron to a target cell across a synapse
What are the criteria of a neurotransmitter?
- The molecule must be synthesised and stored in the presynaptic neurone.
- The molecule must be released by the presynaptic axon terminal upon stimulation.
- The molecules must produce a response in the postsynaptic cell.
Briefly, recap the stages of an action potential?
1: resting state/resting potential
- Approximately -70mV
2: Depolarisation
- If we have a stimulus, we have an event known as depolarisation where the membrane potential becomes more positive due to an influx of sodium ions
3: Rising phase
- More and more sodium channels open and more and more sodium enters the cell, so we reach the peak of the action potential at +30mV
4: Falling phase
- The sodium channels begin to close and the potassium channels open, giving us potassium efflux. The membrane potential becomes more negative
5: Undershoot
- Dips below the resting potential of -70mV. This is because of the slow nature of potassium channels closing, so it can dip below the resting potential before being restored by the sodium-potassium pump.
How do action potentials cause the release of a neurotransmitter?
They arrive at the synaptic button, enabling vgcc to open an calcium to flood into the cell. calcium initiates vesicle fusion with the presynaptic membrane, and then we get a release of the neurotransmitter via exocytosis
What is glutamate?
A major excitatory neurotransmitter in the CNS
How does glutamate synthesis occur?
Via the conversion of glutamine to glutamate, via the enzyme glutaminase, which converts the amide group into glutamate
Describe the transport of glutamate?
Glutamate is transported into vesicles by vesicular glutamate transporters (VGLUT).
There is an H+-Glu transporter on the vesicle membrane. We harness the passive process of H+ moving down its concentration gradient to get more glutamate into the vesicle.
Thus, the intracellular environment of the vesicles is really acidic.
What are the ionotropic glutamate receptors?
- AMPA receptors
- NMDA receptors
- Kainate receptors
What is the response we get when glutamate activates the different ionotropic receptors?
With AMPA, 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+.
With Kainate, we get the influx of Na+ and the efflux of K+.
Describe AMPA receptors?
There are 4 subunit types:
- GluA1
- GluA2
- GluA3
- GluA4
The molecule is referred to as hetero-tetrameric, or the ‘dimer of dimers’. This is because there are normally 2 pairs of two types of subunits. The most common orientation is that one pair is GluA2, and the other pair is GluA1/3/4.
There are four orthosteric binding sites; however, only two sites need to be occupied for the channel to be opened.
The current increases as more binding sites are opened.
The presence of GluA2 subunits prevents Ca2+ flow. Thus, they protect the brain against excitotoxicity.
Describe NMDA receptors?
There are three subunit types:
- GluN1 (or NR1)
- GluN2 (or NR2)
- GluN3 (or NR3)
Hetero-tetrameric. The most common orientation is a pair of GluN1 subunits plus GluN2 (or 3). GluN3 subunits are inhibitory to NMDA receptor function.
NMDA receptors have a unique function: not only are they ligand-gated, but they are also voltage-gated.
We have two ligands: glutamate (major) and Glycine/D-serine. All the sites must be occupied for the channel to open.
With the voltage-gating, there is a molecule of Mg2+ that is blocking the ion channel at rest. It’s only in a depolarised neurone that the Mg2+ would exit the NMDA receptor and allow ions to flow. This depolarisation occurs by the initial stimulation of AMPA receptors, which will allow Na+ into the post-synaptic cell, depolarising it in the process.
How are NMDA receptors dependant on AMDA receptors?
On the post-synaptic cell membrane, the AMPA receptors are activated by glutamate. They allow Na+ into the cell, depolarising it, and thus activating the NMDA receptors by removing the Mg2+ block. The NMDARs allow both Na+ and Ca2+ into the cell, further depolarising the cell.
Furthermore, the Ca2+ causes receptor trafficking, so more AMPARs are made and inserted to the cell membrane surface, enlarging the signal. It also activates CamKinase II (CamKII) which phosphorylates AMPARs, allowing them to pass more current through. This strengthens the synapses and leads to long term potentiation, which strengthens memory.
Describe Kainate receptors?
There are 5 subunit types:
- GluK1 (GluR5)
- GluK2 (GluR6)
- GluK3 (GluR7)
- GluK4 (KA1)
- GluK5 (KA2)
They used to be differently named because they were thought to be AMPA receptors.
The receptor is tetrameric and can be made up of homomers or heteromers. GluK4 and 5 can only form heteromers with GluK1-3 subunits.
It is a ligand-gated ion channel, although we don’t know exactly how many molecules of glutamate are required for the channel to open (since it’s hard to properly crystalise the receptor to study that).
Describe metabotropic receptors?
These receptors are G protein-coupled receptors (GPCRs). They form dimers on the membrane, and there are three types of dimers they can make:
- homomers
- heteromers within groups (e.g. mGlu1 and 5)
- heteromers outside of groups (e.g. mGlu2 and 5-HT2A)
There are 8 subtypes of the receptor (mGlu1-8), and they are divided into 3 subgroups (based on their sequence homology).
GROUP 1: mGlu1, mGlu5
GROUP 2: mGlu2, mGlu3
GROUP 3: mGlu4, mGlu6, mGlu7, mGlu8
Group 1 is predominantly found post-synaptically, while Groups 2 and 3 are predominantly pre-synaptically.
They also bind to different G proteins:
- Group 1 binds to αGq/11, ultimately increasing intracellular Ca2+ release. They contribute to long-term potentiation and therefore plasticity.
- Groups 2 and 3 bind to αGi, ultimately decreasing cAMP formation. They inhibit futher neurotransmitter release.
