Neuro: Neurotransmitters Systems I: Glutamate Flashcards
What is a neurotransmitter?
Chemical messengers that transmit signals from a neuron to a target cell across a synapse
What are the criteria for a molecule to be considered a neurotransmitter?
- The molecule must be synthesised and stored in the presynaptic neuron.
- The molecule must be released by the presynaptic axon terminal upon stimulation
- The molecule must produce a response in the postsynaptic cell
Why must a neurotransmitter be synthesised and stored within the presynaptic neuron?
Because synaptic transmission is extremely fast so there must always be a pool of neurotransmitters ready to be released from pre-synaptic neuron
What is it that triggers the release of neurotransmitters from the pre-synaptic axon terminal?
An action potential
Briefly describe the different stages of an action potential within a neuron
- Cell is at rest so only Na+/K+ pump is open pumping 3 Na+ out and 2 K+ into cell
- Stimulus causes ligand-gated Na+ channels to open leading to influx of Na+ into cell causing depolarisation
- Depolarisation leads to threshold potential being reached leading to activation of voltage-gated Na+ channels
- Activation of voltage-gated Na+ channels leads to more Na+ influx leading to apex of action potential being reached
- Once apex of action potential reached voltage-gated Na+ channels become inactivated and voltage-gated K+ channels open leading to outflow of K+
- Outflow of K+ leads to hyperpolarisation which eventually leads to undershoot - membrane potential reaches below resting potential
- At this point voltage-gated K+ channels close and Na+/K+ pump returns membrane potential back to normal
Briefly describe how an action potential causes synaptic transmission
- Action potential arrives at synaptic terminal and causes ligand-gated Na+ channels to open
- This causes depolarisation to occur which activates voltage-gated Ca2+ channels leading to Ca2+ influx
- Ca2+ influx causes synaptic vesicle to fuse with pre-synaptic membrane
- This causes release of neurotransmitter into synaptic cleft via exocytosis
What neurotransmitter is the major excitatory nuerotransmitter in the CNS?
Glutamate
How is glutamate synthesised within the presynaptic nerve terminal?
- Glutamine is converted into glutamate
- This reaction is catalysed by the enzyme glutaminase
Once glutamate is synthesised within the pre-synaptic neurone how is it stored?
- Glutamate is transported into the synaptic vesicles while H+ ions are transported out of the synaptic vesicles
- This transport is facilitated by vesicular glutamate transporters (VGLUT)
What are the 2 types of glutamate receptor?
- Ionotropic receptors (ligand-gated ion channels)
- Metabotropic receptors (G protein-coupled receptors)
What are the different types of glutamate ionotropic receptor and what agonist activates each one of them?
- AMPA receptors (activated by AMPA)
- NMDA receptors (activated by NMDA)
- Kainate receptors (activated by kainic acid)
What ion do each of the different glutamte ionotropic receptors cause the influx of?
- Na+
- NMDA can also cause influx of Ca2+
What ion do each of the different glutamte ionotropic receptors cause the efflux of?
K+
What are the 4 different AMPA receptor subunits?
- GluA1
- GluA2
- GluA3
- GluA4
What is the most common configuration of AMPA receptor subunits within an AMPA receptor?
- Form tetramers
- 2 GluA2 subunits and any combination of the other 3 subunits (GluA1, GluA3 and GluA4)
How many ligand binding sites are on the AMPA recptors and how many need to be occupied for the AMPA receptor to be activated?
- 4 AMPA receptor binding sites
- At least 2 need to be occupied to cause activation
What does the presence of GluA2 subunits within the AMPA receptor mean for the flow of ions through the receptor?
Presence of GluA2 subunits mean that AMPA receptors are unable to allow Ca2+ influx
What are 3 different NMDA receptor subunits?
- GluN1
- GluN2
- GluN3
What is the most common configuration of NMDA recptor subunits within the receptor?
- Form tetramers
- 2 GluN1 subunits and 2GluN2 or GluN3 subunits
What does the presence of GluN3 subunits mean for the NMDA receptor?
Presence of GluN3 subunits causes NMDA receptor to not function
Apart from glutamate what other ligands are capable of binding to the NMDA receptors?
- Glycine
- D-serine
What NMDA subunit do each of the ligands capable of binding to the NMDA receptor bind to?
- Glutamate binds to GluN2 subunit
- Glycine and D-serine bind to GluN1 subunit
What special property does the NMDA receptor that the other 2 glutamate ionotropic recptors don’t have?
- NMDA receptors are voltage-gated as well as ligand-gated
- This is why NMDA receptors can also cause influx of Ca2+
Because NMDA is a voltage-gated channel it, like the rest of the voltage-gated channels, has to be inactivated during resting potential. What ion is able to inactivate the NMDA receptors?
Mg2+
What is synaptic plasticity and how does glutamate play a role in this?
- Synaptic plasticity is the ability of a synapse to strengthen or weaken
- Repeated stimulation of AMPA and NMDA receptors by glutamate will cause the post-synaptic cell to acquire more AMPA receptors over time - this is called receptor trafficking
- More AMPA receptors means more Na+ influx which eventually leads to activation of enzyme P-CamKII
- This increases ionic conductance of these receptors to influx Na+ even more
- This increase in synaptic plasticity over time is called long-term potentiation
What are the different receptor subunits of the kainate receptors?
- Gluk1
- Gluk2
- Gluk3
- Gluk4
- Gluk5
What are the most common configurations of the Kainate receptor subunits within the receptor?
- Form tetramers
- GluK1-3 can form homomers or heteromers.
- GluK4 & 5 can only form heteromers with GluK1-3 subunits
What are the different types of glutamate metabotropic receptor?
- Group 1
- Group 2
- Group 3
What are some common characteristics of the glutamate metabotropic receptors?
- G protein-coupled receptors
- Venus fly trap domain for ligand binding
- 7 transmembrane domain
- Intracellular C-terminal domain which contains the G-protein
What are the 8 sub-types of glutamate metabotropic receptor and what group do each of theses subtypes fall into?
- Group 1: mGlu1 and mGlu5
- Group 2: mGlu2 and mGlu3
- Group 3: mGlu4, mGlu6, mGlu7 and mGlu8
What are the common configurations of the glutamate metabotropic receptors?
- Form dimers
- Homodimers
- Heterodimers (mGlu1 and mGlu5)
- Can form heterodimers with 5-HT2A receptors (serotonin receptor)
What G protein are each of the groups of glutamate metabotropic receptor coupled to?
- Group 1 coupled to Gq
- Group 2 and 3 coupled to Gi/o
What effect do each of the groups of glutamate metabotropic receptors have on glutamate synaptic transmission?
- Group 1 are post-synaptic and have a role in long-term potentiation
- Group 2 and Group 3 are pre-synaptic and inhibit glutamate release
What transporter is responsible for the re-uptake of glutamate?
Excitatory amino acid transporter (EAAT)
What is excitotoxicity?
Pathological process by which excessive excitatory stimulation can lead to neuronal damage and death
Explain how dysfunctional vesicular glutamate transporters (VGLUTs) can result in glutamate-mediated excitotoxicity
- Dysfunctional VGLUTs mean that glutamate isn’t stored in pre-synaptic vesicles and just stays within cytosol of pre-synaptic neurone
- High glutamate concentrations within pre-synaptic neurone causes excitatory amino acid transporters (EAATs) to reverse function and release glutamate into synaptic cleft
- This causes activation of the AMPA receptors on post-synaptic neurone which will lead to influx of Na+ and depolarisation
- Depolarisation causes activation of NMDA receptors leading to Na+/Ca2+ influx
- High levels of Ca2+ leads to excitotoxicity
What can excessive Ca2+ levels lead to?
- Mitochondrial damage
- Oxidative stress
- Apoptosis - leads to cell death
What conditions are linked with glutamate-mediated excitotoxicity?
- Alzheimer’s disease
- Stroke
- Autism
Name a drug that can be used to reduce glutamate-mediated excitotoxcity and explain how it does this
- Memantine - low-affinity NMDA receptor antagonist
- Blocks NMDA receptor which prevents excessive Ca2+ influx into post-synaptic neurone
