Neuro: Neurotransmitters Systems I: Glutamate

Question 1

What is a neurotransmitter?

Answer 1

Chemical messengers that transmit signals from a neuron to a target cell across a synapse

Question 2

What are the criteria for a molecule to be considered a neurotransmitter?

Answer 2

• 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

Question 3

Why must a neurotransmitter be synthesised and stored within the presynaptic neuron?

Answer 3

Because synaptic transmission is extremely fast so there must always be a pool of neurotransmitters ready to be released from pre-synaptic neuron

Question 4

What is it that triggers the release of neurotransmitters from the pre-synaptic axon terminal?

Answer 4

An action potential

Question 5

Briefly describe the different stages of an action potential within a neuron

Answer 5

1. Cell is at rest so only Na⁺/K⁺ pump is open pumping 3 Na⁺ out and 2 K⁺ into cell
2. Stimulus causes ligand-gated Na⁺ channels to open leading to influx of Na⁺ into cell causing depolarisation
3. Depolarisation leads to threshold potential being reached leading to activation of voltage-gated Na⁺ channels
4. Activation of voltage-gated Na⁺ channels leads to more Na⁺ influx leading to apex of action potential being reached
5. Once apex of action potential reached voltage-gated Na⁺ channels become inactivated and voltage-gated K⁺ channels open leading to outflow of K⁺
6. Outflow of K⁺ leads to hyperpolarisation which eventually leads to undershoot - membrane potential reaches below resting potential
7. At this point voltage-gated K⁺ channels close and Na⁺/K⁺ pump returns membrane potential back to normal

Question 6

Briefly describe how an action potential causes synaptic transmission

Answer 6

1. Action potential arrives at synaptic terminal and causes ligand-gated Na⁺ channels to open
2. This causes depolarisation to occur which activates voltage-gated Ca²⁺ channels leading to Ca²⁺ influx
3. Ca²⁺ influx causes synaptic vesicle to fuse with pre-synaptic membrane
4. This causes release of neurotransmitter into synaptic cleft via exocytosis

Question 7

What neurotransmitter is the major excitatory nuerotransmitter in the CNS?

Answer 7

Glutamate

Question 8

How is glutamate synthesised within the presynaptic nerve terminal?

Answer 8

• Glutamine is converted into glutamate
• This reaction is catalysed by the enzyme glutaminase

Question 9

Once glutamate is synthesised within the pre-synaptic neurone how is it stored?

Answer 9

• 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)

Question 10

What are the 2 types of glutamate receptor?

Answer 10

• Ionotropic receptors (ligand-gated ion channels)
• Metabotropic receptors (G protein-coupled receptors)

Question 11

What are the different types of glutamate ionotropic receptor and what agonist activates each one of them?

Answer 11

• AMPA receptors (activated by AMPA)
• NMDA receptors (activated by NMDA)
• Kainate receptors (activated by kainic acid)

Question 12

What ion do each of the different glutamte ionotropic receptors cause the influx of?

Answer 12

• Na⁺
• NMDA can also cause influx of Ca²⁺

Question 13

What ion do each of the different glutamte ionotropic receptors cause the efflux of?

Answer 13

K⁺

Question 14

What are the 4 different AMPA receptor subunits?

Answer 14

• GluA1
• GluA2
• GluA3
• GluA4

Question 15

What is the most common configuration of AMPA receptor subunits within an AMPA receptor?

Answer 15

• Form tetramers
• 2 GluA2 subunits and any combination of the other 3 subunits (GluA1, GluA3 and GluA4)

Question 16

How many ligand binding sites are on the AMPA recptors and how many need to be occupied for the AMPA receptor to be activated?

Answer 16

• 4 AMPA receptor binding sites
• At least 2 need to be occupied to cause activation

Question 17

What does the presence of GluA2 subunits within the AMPA receptor mean for the flow of ions through the receptor?

Answer 17

Presence of GluA2 subunits mean that AMPA receptors are unable to allow Ca²⁺ influx

Question 18

What are 3 different NMDA receptor subunits?

Answer 18

• GluN1
• GluN2
• GluN3

Question 19

What is the most common configuration of NMDA recptor subunits within the receptor?

Answer 19

• Form tetramers
• 2 GluN1 subunits and 2GluN2 or GluN3 subunits

Question 20

What does the presence of GluN3 subunits mean for the NMDA receptor?

Answer 20

Presence of GluN3 subunits causes NMDA receptor to not function

Question 21

Apart from glutamate what other ligands are capable of binding to the NMDA receptors?

Answer 21

• Glycine
• D-serine

Question 22

What NMDA subunit do each of the ligands capable of binding to the NMDA receptor bind to?

Answer 22

• Glutamate binds to GluN2 subunit
• Glycine and D-serine bind to GluN1 subunit

Question 23

What special property does the NMDA receptor that the other 2 glutamate ionotropic recptors don’t have?

Answer 23

• NMDA receptors are voltage-gated as well as ligand-gated
• This is why NMDA receptors can also cause influx of Ca²⁺

Question 24

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?

Answer 24

Mg²⁺

Question 25

What is synaptic plasticity and how does glutamate play a role in this?

Answer 25

* 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

Question 26

What are the different receptor subunits of the kainate receptors?

Answer 26

* Gluk1 * Gluk2 * Gluk3 * Gluk4 * Gluk5

Question 27

What are the most common configurations of the Kainate receptor subunits within the receptor?

Answer 27

* Form tetramers * GluK1-3 can form homomers or heteromers. * GluK4 & 5 can only form heteromers with GluK1-3 subunits

Question 28

What are the different types of glutamate metabotropic receptor?

Answer 28

* Group 1 * Group 2 * Group 3

Question 29

What are some common characteristics of the glutamate metabotropic receptors?

Answer 29

* G protein-coupled receptors * Venus fly trap domain for ligand binding * 7 transmembrane domain * Intracellular C-terminal domain which contains the G-protein

Question 30

What are the 8 sub-types of glutamate metabotropic receptor and what group do each of theses subtypes fall into?

Answer 30

* Group 1: mGlu1 and mGlu5 * Group 2: mGlu2 and mGlu3 * Group 3: mGlu4, mGlu6, mGlu7 and mGlu8

Question 31

What are the common configurations of the glutamate metabotropic receptors?

Answer 31

* Form dimers * Homodimers * Heterodimers (mGlu1 and mGlu5) * Can form heterodimers with 5-HT_2A receptors (serotonin receptor)

Question 32

What G protein are each of the groups of glutamate metabotropic receptor coupled to?

Answer 32

* Group 1 coupled to Gq * Group 2 and 3 coupled to Gi/o

Question 33

What effect do each of the groups of glutamate metabotropic receptors have on glutamate synaptic transmission?

Answer 33

* 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

Question 34

What transporter is responsible for the re-uptake of glutamate?

Answer 34

Excitatory amino acid transporter (EAAT)

Question 35

What is excitotoxicity?

Answer 35

Pathological process by which excessive excitatory stimulation can lead to neuronal damage and death

Question 36

Explain how dysfunctional vesicular glutamate transporters (VGLUTs) can result in glutamate-mediated excitotoxicity

Answer 36

* 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

Question 37

What can excessive Ca²⁺ levels lead to?

Answer 37

* Mitochondrial damage * Oxidative stress * Apoptosis - leads to cell death

Question 38

What conditions are linked with glutamate-mediated excitotoxicity?

Answer 38

* Alzheimer's disease * Stroke * Autism

Question 39

Name a drug that can be used to reduce glutamate-mediated excitotoxcity and explain how it does this

Answer 39

* Memantine - low-affinity NMDA receptor antagonist * Blocks NMDA receptor which prevents excessive Ca²⁺ influx into post-synaptic neurone