Glutamate

Question 1

4 criteria for a neurotransmitter

Answer 1

chemical messengers

synthesised and stored in pre-synaptic neurone, taken up into vesicles via specific transporter proteins

molecule is released from presynaptic axon terminal upon stimulation (AP, Ca2+ ions for vesicle mobilisation)

produce a response in the post-synaptic cell via diffusion

Question 2

How is glutamate synthesied and stored?

Answer 2

Glutamine > glutamate via glutaminase (substitution of amine group to carboxylic acid group)

Transported into pre-synaptic vesicle via vesicular glutamate transporter (VGLUT)

Counter-transport with H+ via ATP-H+ pump

Question 3

How is glutamate re-uptaken and degraded?

Answer 3

re-uptake: Presynaptic neurones and glial cells have Na+ dependant amino acid transports (EAATs) - transfer glutamate back into presynaptic cell bulb or glial cell

glutamine is transported out of glial cells via SN1 then into neurone via SAT2

degradation: glutamate -> glutamine via glutamine synthetase

Question 4

what are the 3 ionotropic glutamate receptors? And where are they found?

Answer 4

all post-synaptic, named after agonists, influx of Na+ and efflux of K+ (NMDA also allows Ca2+)

AMPA - GluA1-4 = heterotetrameric structure, forming 4 orthosteric binding sites, at least 2, GluA2 prevents Ca2+ flow = excitotoxicty help

NMDA - GluN1-3 = heterotetrameric, ligand and voltage gated, glutamate for GluN2, glycine/D-serine for GluN1 GluN3 are inhibitory, requires 4, Mg2+ ion block at resting

Kainate - GluK1-5, 1-3 can form homers or heteromers, 4&5 only heteromers with 1-3

Question 5

What are the 3 groups of metabotropic receptors and their subtypes?

Answer 5

Group 1 - mGlu1 & 5
Group 2 - mGlu 2 &3
Group 3 - mGlu 4,6,7,8

Question 6

What is the effect of Group 1 activation

Answer 6

Gq coupled - PIP2 -> GAG and IP3

IP3R activation on ER = ^Ca2+

Synaptic plasticity and long-term potentiation

Question 7

What is the effect of Group 2 & 3 activation

Answer 7

Gi/o coupled = down-regulates AC

↓cAMP formation

Inhibit NT release

thus auto-receptors on presynaptic membrane

Question 8

How to treate glutamte-mediated excitotoxicity in Alzheimer’s disease

Answer 8

Memantine - NMDA receptor antagonist, blocking

Question 9

What are the mechanisms of long term potentiation?

Answer 9

Glutamate activates AMPA receptor

depolarisation

NMDA receptors open due to depolarisation (Mg2+ removed)

Ca2+ enters the cell, activating post-synaptic protein kinases such as calmodulin kinase 2 and PKC

leading to insertion of new AMPA receptors in post synaptic membrane

inceases glutamate sensitivity and ion channel conductance