Lecture 2 - Glutamate

Question 1

What are the 5 core components of a neurotransmitter?

Answer 1

1. It is synthesised by enzymes
2. Transporters move it into cells
3. Transporters move it into vesicles
4. It activates receptors
5. Molecules terminate their action

Question 2

How do the 5 core components relate to glutamate?

Answer 2

1. Endogenous synthesis via many routes (non-essential amino acid)
2. Mainly EAAT2
3. VGLUT1-3
4. AMPA, NMDA, Kainate, mGluR

Question 3

What triggers vesicle exocytosis?

Answer 3

Calcium influx

Question 4

How is glutamate in the synaptic cleft re-uptaken?

Answer 4

Transported into astrocytes by EAAT1/2
Broken down into glutamine by glutamine synthase
Glutamine pumped into extracellular space by glutamine transporter
Glutamine uptaken by presynaptic membrane
Converted back into glutamate by glutaminase

Question 5

Describe the general structure of an ionotropic glutamate receptor

Answer 5

Tetramer (4 subunits)
Extracellular N terminus
Intracellular C terminus
3 transmembrane domains
1 partly transmembrane domain that forms the pore

Question 6

What subunits make up the

• AMPA receptor
• NMDA receptor
• Kainate receptor

Answer 6

AMPA = GluA1-4
NMDA = GluN1-3
Kainate = GluK1-5

Question 7

What determines the permeability of an AMPA receptor to Calcium?

Answer 7

The GluA2 subunit has a site in the amino acid chain that can be Q (glutamine) or R (arginine). Glutamine allows permeability to calcium. Arginine makes it impermeable.

Question 8

Which ions are the following receptors permeable to?

• AMPA receptor
• NMDA receptor
• Kainate receptor

Answer 8

AMPA = Na+, K+, sometimes Ca2+
NMDA = Mainly Ca2+, also Na+
Kainate = Na+ and K+

Question 9

What specific kind of structure does the NMDA receptor have?

Answer 9

Heterotetramer - must have two GluN1 subunits and two GluN2 subunits

Question 10

What 3 things are required for NMDA receptor activation?

Answer 10

1. Agonist binds to main receptor site
2. Glycine or D-serine binds to modulatory site
3. The Mg2+ block is removed by depolarisation mediated by Na+ influx through AMPA receptors

Question 11

Which neurotransmitters are the ‘fast’ neurotransmitters (act through ionotropic receptors)?

Answer 11

Glutamate, GABA, Glycine, (amino acids)
Ach, 5-HT, (biogenic amines)
ATP

Question 12

What are the 3 groups of mGluRs and what G protein are they coupled to?

Answer 12

Group 1: mGlu1, mGlu5, Gq
Group 2: mGlu2, mGlu3, Gi/o
Group 3: mGlu4, mGlu6-8, Gi/o

Question 13

What is the location and function of each mGluR group?

Answer 13

Group 1: Postsynaptic, slow excitatory, increases intracellular calcium
Group 2 + 3: Presynaptic, inhibitory

Question 14

Name an agonist, antagonist and positive allosteric modulator of the AMPA receptor

Answer 14

Agonists: AMPA, Glutamate
Antagonists: NBQX, Telampanel
PAM: Cyclothiazide, Ampakines

Question 15

Name an agonist and antagonist of the NMDA receptor

Answer 15

Agonists: NMDA, Glutamate, Aspartate
Antagonists: AP5

Question 16

Name an agonist and antagonist of the Kainate receptor

Answer 16

Agonists: Kainate, Glutamate, Demoic acid
Antagonists: CNQX, ACET

Question 17

What is the location and function of each ionotropic glutamate receptor?

Answer 17

AMPA: Postsynaptic, fast excitatory
NMDA: Postsynaptic and presynaptic, slow excitatory (LTP/synaptic plasticity, excitotoxicity)
Kainate: Postsynaptic excitatory, presynaptic inhibition

Question 18

How many genes are there for the GluN1 and GluN2 subunits?

Answer 18

GluN1 = single gene with 8 splice forms
GluN2 = 4 different genes

Question 19

On which subunits of the NMDA receptor is the agonist binding site, modulatory site and allosteric site located?

Answer 19

GluN2 = Agonist binding site 
GluN1 = Modulatory site, Allosteric site

Question 20

What are the effects of ketamine?

Answer 20

Medication causing anaesthesia, pain relief, sedation and memory loss

Question 21

How does ketamine work?

Answer 21

Selective antagonist of the NMDA receptor