Lecture 2- Amino acid neurotransmitters Flashcards
Why was it hard to identify these NTs?
Because they are dietary amino acids so are very common in the money. e.g. glutamine, GABA
Serotonin etc. were located to neurones so it was more obvious they were NTs.
What’s the problem with the dietary amino acids as NTs?
Brain has to protect itself from fluctuations in the dietary amino acids that go up and down when you eat.
Blood brain barrier permeability allows only the right amount in. So drugs that increase or affect these amino acids are not used because wouldn’t make a difference to how much in brain. Instead, the drugs target the receptors. E.g. glutamate receptors only found in neurone.
Glutamate main features?
Major excitatory NT.
Stored in vesicles, released in Ca2+ -dependent manner (like all NTs).
Has a transporter protein to uptake into synaptic vesicles. (vesicular glutamate transporter, vGluT)
another transporter protein to mop up released glutamate from the cleft into neurones and particularly into glia. (EAAT)
Describe the glutamate shunt. With the release and uptake of glutamate. (Recycling to save energy.)
- Glutamate, the precursor is made into glutamate by glutaminase.
- VGluT packages glutamate into vesicles.
- AP causes Ca2+ entry causes glutamate release.
- Small fraction of glutamate finds its receptor. Rest is mopped up by EAAT in neurone and glia, to recycle. (Excitatory amino acid transporter.)
- In glia, the glutamate is made into glutamine and then transported out and into the neurone by GlnT (glutamine transporter).
6.
What is VGluT?
The vesicular glutamate transporter, localised in the synaptic vesicle membrane. Gets glutamate into vesicles. It’s an antiport, pumps in glutamate at the expense of protons, down their concentration gradient.
Why are the vesicles full of H+ for the VGluT to swap for glutamate?
The vesicles are filled with protons by VATPase. Which burns a lot ATP. 1/3 of all atp made gets used by the nervous system.
What are the 2 types of glutamate receptor?
- Ionotropic- ligand-gated cation channel.
Receptor is directly linked to pore where the cation goes through.
Fast- 10s of miliseconds - Metabotropic- G-protein coupled.
Receptor activated second messenger based cascade of events.
Slow. 100s of miliseconds up to a second.
What are the 3 major classes of ionotropic receptors?
- AMPA
- Kainate
- NMDA
Named by their specific (kind of) agonists. All of these are activated by glutamate too.
Homo or heteromeric of 4 subunits, forming a pore-loop structure. 16 different subunits available and sub groups.
This mean that glutamate can cause lots of different responses because different receptors that all are activated by glutamate.
Describe AMPA receptors
mediate fast synaptic transmission
Fast EPSP
Non-specific cation channels.
When open sodium goes in and k goes out. Driven by electrochemical gradient. Na higher on outside, K higher on inside.
But lots more Na goes in because of the gradient. So get depolarisation.
Relative permeability to Na+, K+ (and Ca2+) depends on sub-unit structure. (There’s a moderate permeability to calcium)
4 sub-units, each a receptor for Glu, needs 2 occupied to be activated. Need 2 glutamate to be activated.
Kainate receptors
Similar to AMPA receptors. ONly difference is, less widespread in the CNS and mostly on pre-synaptic terminals.
The cell needs to know how much glutamate it’s releasing. So these in the presynaptic membrane feedback to the cell.Most variants are very impermeable to calcium, some a bit better.
Opening causes fast depolarisation. you get an epsp, if it’s big enough the post-synaptic cell fires an AP.
NMDA receptors are special why?
For two reasons.
1. compared to the ampa and kainate, NMDA are highly permeable to calcium. They let Na and k through, but also calcium
- At the normal state. The channel is blocked by a magnesium iron. At resting membrane potential about -60mV. The outer pore opens and a magnesium ion sits in it. Even if you add glutamate, the channel wont open because the magnesium is stuck in it. Needs depolarisation to occur in post synaptic neurone for channel to open. to aboutb -40mV. Then when glutamate binds with deoplarised voltage the magnesium is ejected.
Activation also requires glycine. (which is normally an inhibitory Nt)
What does NMDA need to open?
- Depolarisation
- Glutamate
- cofactor- glycine
patch clamp slides
don’t understand..
Metabotropic receptor family
How many receptors?
Divided into which categories?
(not really targets for drugs)
Eight different receptors mGluR1-8
No sequence homology with any other G-protein coupled receptors
Divided into 3 groups:
Group 1 (mGluR1, mGluR5) Somatodendritic location. Find up in top of neurone in cell body and dendrites so can modify how a cell responds to synaptic input.
Group 2 (mGluR2, mGluR3) Somatodendritic location and nerve terminal location. modify how cell releases glutamate.
Group 3 (mGluR4, mGluR6, mGluR7, mGluR8) nerve terminal location , both pre and post synaptic.
summary of what happens when glutamate released from pre synaptic cell?
For a low frequency brief stimulus:
Glutamate is released. And it preferentially acts on the AMPA receptor.
This causes a depolarisation. an EPSP, and if this EPSP is big enough this cell might fire an action potential.
The NMDA will not activate because the magnesium is stuck in there.
For a high frequency of APs:
Lots of glutamate released. Lots of AMPA receptors activated. The post synaptic cell depolarises to about -40mV and stays there long enough to eject the magnesium from NMDA receptor. This then activates and calcium comes in.
So a single release of glutamate will only activate AMPA. But a high freuqency burst, then the calcium comes in through nmda and causes lots of changes in the cell. Can signal for more receptors to be made and can change gene transciprtion. So long term changes. So NMDA is more long term, memory and learning. The magnesium block is why it can do this.
