NEURO: Neurotransmitter Systems I: Glutamate Flashcards
What are neurotransmitters?
What are the major central neurotransmitters?
chemical messengers that transmit signals from a neurone to a target cell across a synapse (e.g. neurotransmission)
Acetylcholine Glutamate GABA Glycine Monoamines
What is neurotransmission?
the process that drives information between neurones and their targets
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.
What is the major excitatory neurotransmitter?
glutamate
Nearly all excitatory neurons in the CNS are glutamatergic
Describe the synthesis of glutamate.
This type of neurotransmitter is known as an amino acid transmitter because its precursors are all amino acids.
Glutamine is converted to glutamate in nerve terminals, which is catalysed by glutaminase, which is phosphate-activated. It is synthesised in the nerve terminals.
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.
Describe glutamine reuptake and degradation
Glutamate Receptors
Ionotropic Receptors:
· AMPA Receptors
· NMDA Receptors
· Kainate Receptors
Metabotropic Receptors:
· Group I
· Group II
· Group III
What is the response 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.
What do GluA2 subunits do?
There are 4 subunit types (plus alternative splice variants):
- GluA1
- GluA2
- GluA3
- GluA4
hetero-tetrameric - there are normally 2 pairs of two types of subunits. The most common orientation is GluA2 and GluA1/3/4.
The presence of GluA2 subunits prevents Ca2+ flow. Thus, they protect the brain against excitotoxicity.
How many binding sites does the AMPA receptor have? How many must be occupied for channel opening?
What are AMPA receptors most commonly comprised of?
Four orthosteric binding sites
Two sites must be occupied for channel opening
Current increases as more binding sites are occupied
- 2 GluA2 subunits
- 2 GluA1/3/4 subunits
Describe NMDA receptors.
What are NMDA receptors mostly comprised of?
There are three subunit types (plus alternate splice variants):
- GluN1 (or NR1)
- GluN2 (or NR2)
- GluN3 (or NR3)
It is also hetero-tetrameric.
The most common orientation is a pair of GluN1 subunits plus GluN2 (or 3). GluN3 subunits are inhibitory to NMDA receptor function.
What do GluN3 subunits do?
inhibit NMDA receptor function
Types of NMDA glutamate receptors
How many binding sites must be occupied for channel opening in NDMA receptors?
Ligand NMDA glutamate receptor
Ligand and Voltage-gated NMDA receptors
All the sites must be occupied for the channel to open.
> Glycine or D-serine binds GluN1
Glutamate binds GluN2
Voltage-gated NMDA glutamate receptor, how does it work?
> 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
Synaptic Plasticity
the ability of synapses to modify their strength
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)
How are NMDA receptors dependant on AMDA receptors?
On the post-synaptic cell membrane, the AMPA receptors are activated first. They allow Na+ into the cell, depolarising it, and thus activating the NMDA receptors. The NMDARs allow both Na+ and Ca2+ into the cell, further depolarising the cell.
Furthermore, the Ca2+ traffics more AMPARs to the cell membrane surface, enlarging the signal. It also activates an enzyme called CamKinase II (CamKII) which phosphorylates AMPARs, allowing them to pass more current through. Effectively, it increases their permeability.
Describe how the NMDA and AMPA receptors play a role in long-term potentiation, and what implications that mechanism has.
Because of the actions of the NMDARs and AMPARs, we now have more receptors on our membrane, and we have an increased ion flow. This causes an increased response induced in the post-synaptic cell.
This potentiation is deemed long-term because we’ve had more proteins inserted into the membrane and phosphorylated. These changes aren’t readily reversible.
This is thought to be a very important mechanism in what is known as synaptic strengthening and also in learning and memory (mostly mediated by calcium influx).
Describe Kainate receptors.
5 subunit types:
- GluK1
- GluK2
- GluK3
- GluK4
- GluK5
tetrameric 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 is 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
Glutamate metabotropic receptors
8 subtypes divided into 3 groups coupled to different G-proteins:
> Group 1 (Gq)
- leads to an elevation in Ca2+
- important in long-term potentiation (LTP)/plasticity and transcription/translation
> Groups 2&3 (Gi/o)
- 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
