Neurotransmitters 1: Glutamate, GABA & Acetylcholine Flashcards
What is a neuronal output determined by?
- The number of excitatory and inhibitory synaptic inputs
- Strength of individual responses
- Both of these together
What are the two generalised categories of transmitters?
Excitatory (depolarise towards threshold potential to generate an action potential)
Inhibitory (no action potential will be generated)
How can transmitters activate ion channel activity?
- Transmitter release from pre-synaptic terminals
(modifying the voltage gated calcium channels) - Controlling excitatory of post-synaptic neuron (controlling the potassium channels to determine number of action potentials)
Why is the timing of inhibitory and excitatory inputs important?
If the potentials arise close in time, they can be added together to cause an action potential.
The timing of the excitatory and inhibitory inputs are important. The inhibitory input will dampen down the excitatory one.
What is the main excitatory neurotransmitter in the CNS?
Glutamate (an amino acid)
What are some of the prominent glutamatergic pathways in the CNS?
- Cortico-cortical pathways are important in information processing and can modulate loss of neuron activity.
- Pathways between the thalamus and the cortex. This link helps modulate the thalamus. The thalamus is important in controlling all out senses except smell.
- Glutamate is also important in the pathway between the cortex and the striatum. This pathway regulates involuntary movement.
- Glutamate projects between the palladium which has a role in motor control
What are the main roles of glutamate transmission? (what does it help with in body)
Memory, emotions and cognition.
Psychiatric conditions including depression, anxiety and drugs addiction.
Role in some excitotoxic disorders - abnormal activities in brain leading to neuronal damage
How is glutamate synthesised and what can it not do?
It cannot cross the blood-brain barrier meaning that it is not supplied by circulation.
How it is synthesised?
The citric acid cycle produces -ketoglutarate which is converted to glutamate by enzymes.
What is the concnetrsion of the neurotransmitter in the cytoplasms of neurons compared to the somatic vesicle membranes?
In the cytoplasm of neurons, it is at concentration of 1millimolar. This is taken up be transported of the somatic vesicle membranes which concentrate the glutamine from 20-100 millimolar.
Using glutamate as the neurotransmitter, what happens when an action potential invades the pre-synaptic terminal?
When an action potential invades the pre-synaptic terminal, it depolarises the neurone, voltage gates calcium channels open, calcium enters which triggers exocytosis of synaptic vesicle contents.
Glutamate is released and diffuses across the synaptic cleft to interact with receptors on the post-synaptic membrane.
It then diffuses out of the synaptic cleft where it encounters transporters for glutamate located in the membrane of surrounding astrocytes.
Astrocytes are packed very close to the synaptic terminal. Glutamate is taken up into the astrocyte via these transporters where is can combine with glutamate synthesised inside the astrocyte.
Within the astrocyte, the glutamate is then converted via glutamine synthase enzymes to glutamine. The glutamine is kicked out of the astrocyte via a glutamine exporter into the extra-cellular space. The glutamine is then taken up by the neuron by a glutamine transporter and then glutamine is then acted on by the glutaminase enzyme and converted into glutamate.
Completion of the cycle.
What are the two types of glutamate receptors?
- Ionotrophic receptors (ion channels)
- Glutamate binding site located on channel
- Binding promotes channel opening
- Role in fast synaptic transmission
(Each receptor is made up of 4 subunits which form a doughnut structure around a ore region. When glutamine binds to extra-cellular domain it induces a conformation change to open the pore region to allow ion (sodium, calcium or potassium) to pass through the channel to depolarise the membrane)
- Metabotrophic receptors
- G protein coupled receptors with a 7 transmembrane structure
- Modulate excitation and synaptic transmission
What are the 3 types of ionotrophic glutamate receptor?
NMDA receptor
AMPA receptor
Kainate receptor
(For all of them in the brain, glutamate is the natural transmitter. NMDA, AMPA and Kainate do not exist in our brains.)
What do NDMA and AMPA receptors work to cause?
Responsible for depolarising synaptic transmission.
Activation of AMPA and NMDA is responsible for lots of the fast transmissions in the CNS.
AMPA - fast synaptic current with fast decay, influx of Na+ ion depolarised neurons, block of the receptor will have a major inhibitory effect on CNS
NMDA - slower onset and slower decay, high affinity glutamate binding, influx of Na+ and Ca2+, calcium entry can modulate activity of calcium dependant kinases and phosphatases involved in longer term changes in neuronal behaviours such as gene expression. block of NMDA receptors can have an affect on behaviour and memory
How do NDMA and AMPA work together to depolarise?
AMPA - gives an indication of glutamate conc in synaptic cleft. Glutamate is released at a high conc, rises and then diffuses out the cleft and taken up by the transporters in the astrocyte membrane, bringing the concentration rapidly down to 0.
When conc is high, glutamate forms a complex with NMDA, the pore will open and ions will flow. Only when the pore is closed can the agonist (glutamate) dissociate. Glutamate has a low affinity for the receptor so can only bind when there is a high concentration.
When glutamate diffuses out of cleft and concentration is low, glutamate rapidly dissociates from the receptor and terminates the AR complex.
NMDA - has a slow onset and offset.
Although it binds glutamine very well, the channel is blocked by magnesium ions. Magnesium is + charged and the inside of the neuron is negative so magnesium will want to go to the negative interior of neuron. Unfortunately, it does not fit and blocks the receptor. The pore is open but the sodium and calcium ions cannot pass.
As the AP depolarises the neuron, the neuron becomes less positive so the magnesium is not as attracted so it can diffuse out of the NMDA receptor and allow sodium and calcium ions to enter. The growth of the NMDA receptor therefore takes longer as the magnesium needs to leave.
This means the glutamate doesn’t dissociate very easily so stays stuck on the receptor. The channel will therefore be opening and closing but the glutamate will not come off. Even tho the glutamate concentration is getting less, the receptor continues to be activated by the highly bound glutamate.
Give some detail on metabotrophic glutamate receptors
From amino acid sequencing, we know there are 8 different metabotrophic glutamate receptors.
Each of these is a 7 transmembrane receptor.
These receptors can be located either pre or post synaptically and glutamate released from pre-synaptic neuron can act on the pre-synaptic terminal or an adjacent neuron.
It could feed back onto itself or the glutamate could act on the post-synaptic receptor.
Pre synaptic:
The affect of activating the pre-synaptic metabotrophic receptor it to inhibit voltage gated calcium channels. This means less calcium influx into pre-synaptic terminals so less release of transmitter.
As a g protein couple receptor, it is coupled to g protein components which are alpha, beta and gamma subunit. Upon action, GTP displaced GDP bound to the alpha sub unit and the alpha subunit then has action on adenyl cyclase. For the pre-synaptic inhibitor, the beta and gamma units interact directly with voltage gated ion channels and reduce their activity.
The beta and gamma subunits can also act directly on the synaptic vesicle process and reduce its exocytosis.
Post synaptic:
Glutamate can also activate post-synaptic metabotrophic receptors and the outcome of this is to modify potassium channels which modules the excitability of neuron.
After activation of the glutamine receptor, the beta gammas subunits can interact with the voltage gated calcium channels.
There is also a direct interaction of potassium channels in the post-synaptic membrane. When these channels are activated, there is a slow effect (due to it being a G receptor rather than an ion channel) taking a couple of seconds. The effect is to hyperpolarise the membrane (more negative cell). This leads to the number of action potentials decreasing.
