Glutamate

Question 1

What is glutamate

Answer 1

1. The Main excitatory transmitter in the CNS

Question 2

What type of receptor does glutamate bind to

Answer 2

1. Amino acid receptor

2. Activates a large family of receptors

Question 3

What is glutamate synthesised from

Answer 3

1. Glutamine

Question 4

How is glutamate action terminated

Answer 4

1. Action terminated- Reuptake by the Excitatory Amino Acid Transporters (EAAT)
2. Aspartate and N-acetylaspartyl glutamate (NAAG) may also play a role

Question 5

Describe the process of glutamine synthesised

Answer 5

1. Glutamine is exported out of glial cells by glutamine transporters
2. Glutamine transporters are proteins inserted into cell membrane that are specific for transporting glutamine
3. Glutamine transporters present on nerve terminals transport glutamine into presynaptic nerve terminal
4. At mitochondria it meets phosphate activated glutaminase which converts it to glutamate
5. Glutamate transported into synaptic vesicles by vesicular transporter
6. When nerve terminal is depolarised the vesicles fuse with membrane releasing glutamate into synapse
7. Glutamate acts at postsynaptic receptors

Question 6

What are glial cells

Answer 6

1. Glial cell- non neuronal but involved in function of brain

Question 7

How is glutamate recycled

Answer 7

1. Recycled back into nerve terminals
2. Taken up by EAAT
3. Some is taken up into glial cells where glutamine synthase converts glutamate back into glutamine

Question 8

Are glutamate receptors ionotropic or metabotropic

Answer 8

1. Can be both

Question 9

Describe ionotropic glutamate receptors

Answer 9

1. 3 classes
   - NMDA
   - AMPA
   - KA
2. Subunits for each class
3. Specific agonists which activate receptors give the name to the ionotropic glutamate receptor

Question 10

Describe metabotropic glutamate receptors

Answer 10

1. Split into 3 groups
2. Group I - Stimulate IP3 and Ca2+
3. Group II- Decrease CAMP
4. Group III- Decrease CAMP
5. Divided into groups based on G-protein coupling mechanism and downstream intracellular signalling pathway that is activated

Question 11

How does glutamate bind to so many receptors

Answer 11

1. It is not a rigid molecule
2. Different constituents can rotate along two different axes
3. Can adopt different conformations
4. Rotates about the alpha-beta and beta-gamma bonds
5. Nine ‘rotamers’ are possible

Question 12

Describe structure of ionotropic glutamate receptor

Answer 12

1. Subunits have 4 membrane segments
2. 1, 3 and 4 are trans-membrane segments
3. 2 does not span the membrane (p-element)
4. 4 subunits to a receptor (tetrameric)
5. P-elements face inward and form channel.
6. Subunits differ in structure
7. Subunit composition determines properties

Question 13

Describe AMPA receptor structure

Answer 13

1. Homomeric- all made up of same subunits
2. Heteromeric – One different subunit inserted
3. Has different amino acid sequence and properties

Question 14

Describe NMDA receptor structure

Answer 14

1. No homomeric
2. Heteromeric- must always have GluN1
3. Any combination of the other subunits

Question 15

Describe AMPA

Answer 15

1. AMPA = alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
2. Ligand gated ion channel
3. Permeable to Na+ in and K+ out
4. Ca2+ if no GluA2 subunit
5. fast excitatory transmission

Question 16

What are agonists of AMPA

Answer 16

1. glutamate,
2. AMPA- most potent which is why it is called AMPA receptor
3. KA

Question 17

What are the antagonists of AMPA

Answer 17

1. NBQX (competitive)

2. GYKI 53655 (non-competitive)

Question 18

Describe NMDA receptor

Answer 18

1. NMDA = N-methyl-D-aspartate
2. Pass Na+, K+ and Ca2+
3. Voltage and ligand gated
   - Voltage sensing- key to function
4. 1 GluN1 subunit plus 3 GluN2A-D subunits
   - GluN1 is obligatory
5. Slow and long lasting

Question 19

What is needed along with glutamate to activate NMDA receptor

Answer 19

1. glycine/serine co-agonist
2. must be bound in order for glutamate to activate receptors
3. plentiful supply in brain

Question 20

What are the agonists of NMDA receptors

Answer 20

1. NMDA
2. glutamate
3. aspartate

Question 21

What are the antagonists of NMDA receptors

Answer 21

1. 2-AP5, CPP (competitive);

2. PCP, Ketamine, MK801 (non-competitive)

Question 22

What gives the different time courses of postsynaptic EPSP

Answer 22

1. glutamate binds both kinds of receptors at most synapses
2. The different properties of AMPA (fast and short lasting) and NMDA (slow and long lasting) receptors gives a fast and slow time course to the postsynaptic EPSP

Question 23

Describe dual gating of NMDA receptors

Answer 23

1. glutamate alone - no current flows as Mg2+ blocks channel
2. depolarisation relieves Mg2+ block- requires change in voltage
3. Ca and Na flow through channel
4. large slow depolarization
5. so – NMDA receptors need agonist + depolarisation to work
6. thus, they can act as transmitter and voltage sensors
7. Mg-dependent gating is very important in synaptic plasticity, learning and memory

Question 24

Describe metabotropic glutamate receptors

Answer 24

1. mGluRs
2. GPCRs
3. 7-transmembrane regions
4. Not involved in fast excitation
5. Slow, neuromodulatory role
6. Many types, connected to different second messenger systems

Question 25

Describe mGluR actions with ion channel

Answer 25

``` Channels normally allow Ca++ in 1. Glutamate activates mGluR 2. Leads to Ca-channel closure - reduced Ca++ influx 3. Controls transmitter release Channels normally allow K+ out 1. Glutamate activates mGluR 2. Leads to K-channel closure - reduced K-efflux 3. Leads to slow depolarization ```

Question 26

How can mGluR cause release of Ca2+

Answer 26

1. Activation of intracellular enzyme 2. Initiation of second messenger cascade 3. Ca2+ release from intracellular stores 4. Multitude of effects 5. Further enzyme activation 6. Opening/closing of ion channels 7. Modulation of postsynaptic excitability 8. Very important in excitotoxicity and neurodegeneration

Question 27

Roles of different mGluRs

Answer 27

1. mGluR1 and mGluR5 postsynaptic produce slow depolarisation, release Ca2+ from intracellular stores 2. mGluR2, 3, 4, 7 & 8 presynaptic, usually inhibit glutamate (and other transmitters) release by decreasing Ca influx 3. Different receptors are location, synapse and tissue specific

Question 28

Describe how presynaptic glutamate receptors control release of glutamate

Answer 28

1. Presynaptic- NMDA, mGluR and KAR 2. Controls glutamate transmitter release 3. mGluR- inhibits transmitter release 4. NMDA- promotes transmitter release 5. presynaptic NMDAr increase glutamate release by increasing Ca influx 6. presynaptic mGluR decrease glutamate release by decreasing Ca influx