Neurotransmitter System I: Glutamate

Question 1

RECAP: What is neurotransmission?

Answer 1

The fundamental process that drives information transfer between neurons and their targets

Question 2

What are neurotransmitters?

Answer 2

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

Question 3

What is the criteria for neurotransmitters?

Answer 3

• Molecule must be synthesised and stored in the pre synaptic neuron
• The molecule must be released by the pre-synaptic axon terminal upon stimulation
• The molecule must produce a response in the post synaptic cell

Question 4

What can neurons be classified by?

Answer 4

• Can be classified by the neurotransmitter they use
• These differences arise due to the differential expression of proteins involved in neurotransmitter synthesis, storage and release

Question 5

What is Glutamate?

Answer 5

• A major excitatory neurotransmitter in the central nervous system (CNS)
• It took a lot of time to realise that glutamate was a neurotransmitter
• It’s a crossroad of multiple metabolic pathways

Question 6

How is glutamate synthesised and stored for storage?

Answer 6

• Glutamine -> Glutamate via Glutaminase (phosphate activated)
• Synthesised in the nerve terminals
• Transported into vesicles by vesicular glutamate transporter (VGLUT)
• Counter transport with H+ to drive glutamate entry into vesicles

Question 7

Describe the re-uptake of glutamate

Answer 7

• Neurons go from the pre-synaptic terminal to the post-synaptic neuron
• Neurons and glial contains Na+ dependent excitatory amino acid transporters (EAATs)

Question 8

Describe the Degradation of glutamate

Answer 8

Glutamate -> Glutamine via Glutamine synthetase -> Glial cells -> Nuerons via SN1 and SAT2
- SN1 = System N transporter (expressed on glial cells)
- SAT2 = System A transporter 2 (expressed on neurons)

Question 9

Describe the neurotransmitter receptors

Answer 9

• There are two broad families of neurotransmitter receptors
• Ligand gated ion channels (ionotropic)
• G protein coupled receptors (metabotropic)

Question 10

List the glutamine ionotropic receptors

Answer 10

• AMPA receptors
• NMDA receptors
• Kainate receptors

Question 11

List the glutamate Metabotropic receptors

Answer 11

• Group 1
• Group 2
• Group 3

Question 12

Describe ionotropic glutamate receptors
List different types of receptors with their influx and efflux

Answer 12

Ionotropic glutamate receptors are named after agonists that activate them

Question 13

List different types of ionotropic glutamate receptors with their influx and efflux

Answer 13

Receptor: AMPA Influx: Na+ Efflux: K+
Receptor: NMDA Influx: Na+/Ca2+ Efflux: K+
Receptor: Kainate Influx: Na+ Efflux: K+

Question 14

Describe AMPA receptors

Answer 14

• Four subunit types (plus alternate splice variants)
• GluA1, GluA2, GluA3, GluA4
• Has a hetero tetrameric structure

Question 15

Describe the basis of a Hetero tetrameric

Answer 15

Hetero tetrameric: Dimer of dimers
- 2 GluA2 subunits
- 2 GluA1, 3 or 4
- Four orthosteric binding sites
- Two sites must be occupied for channel opening
- Current increases as more binding sites are occupied

Question 16

Describe NMDA receptors

Answer 16

Three subunit types: GluN1, GluN2, GluN3
- Organised into a hetero tetrameric structure
- Most commonly: 2 GluN1 and 2 GluN2 subunits or GluN3
- GluN3 subunits are inhibitory to NMDA receptor function

Question 17

What type of receptors are NMDA receptors?

Answer 17

• NMDA receptors are both ligand and voltage gated
• Ligands: Glutamate and glycine or D serine
• All sites must be occupied for channel opening

Question 18

Describe Kainate receptors

Answer 18

• 5 subunit types: GluK1,GluK2,GluK3,GluK4,GluK5
• Organised into a tetrameric structure
• GluK1-3 can form hormomers or heteromers
• GluK4 & 5 only heteromers with GluK1-3 subunits

Question 19

What type of receptors are Kainate receptors?

Answer 19

Ligand gated ion channels:
- Glutamate binding required for channel opening
- Limited distribution in the brain compared to AMPA/NMDA receptors

Question 20

Describe metabotropic glutamate receptors

Answer 20

G protein coupled receptors
8 sub types: MGlu1,MGlu2,Mglu3,MGlu3,MGlu4,MGlu5,MGlu6,MGlu7,MGlu8,MGlu9
- Are dimers: Homomers, Heteromers: e.g. mGlu1 and mGlu5, Heteromers: e.g. mGlu2 and 5 HT2A