Neurotrsnamitters system 1:glutamate

Question 1

what are neurotransmitters?

Answer 1

chemical messengers that transmit signals from a neuron to a target cell across a synpase (neurotransmission)

Question 2

what are the 3 criteria of a neurotransmitter?

Answer 2

1)NT must be synthesised and stored in the pre-synaptic neuron
2)Upon stimulation the NT must be released from the pre-snypatic axon
3)The molecule must produce a reponse in the post-synaptic cell

Question 3

NT is one method of classifying neurons. why is this possible?

Answer 3

Since the NT released from different neurons can be different and this is because of differential expression of different proteins involved in NT synthesis, storage and release.

Question 4

what type of NT is glutamate? (excitatory or inhibitory)

Answer 4

An excitatory neurotransmitter of the CNS

Question 5

What is the precursor of glutamate?

Answer 5

Glutamine

Question 6

what is the enzyme used to convert glutamine into glutamate?

Answer 6

Phosphate-activated Glutaminase

Question 7

Once glutamine is converted into glutamate via phosphate-activated glutaminase. What happens to the glutamate made?Describe this process

Answer 7

The Glutamate is transported into vesicles via Vesticular glutamate transporter (VGLUT).

Question 8

What is the mechanism by which Vesticular glutamate transporter (VGLUT) transports glutamate into vesicles?

Answer 8

Counter transport with H+ to drive Glutamate Into the vesicle (H+ out glutamate in)

Question 9

Why do the H+ leave the vesicles via VGLUT?

Answer 9

since there is already an acidic environment inside of the vesicle.

Question 10

which part of VGLUT is active and which is passive?

Answer 10

Moevemtn of H+ out = passive (down the conc gradient)
Movement of Glutamate in=active

Question 11

exocytosis of glutamate results in?

Answer 11

the release of glutamate into the synaptic cleft

Question 12

How do we get re-uptake of glutamate in both neurons and gilal cells?

Answer 12

Via excitatory amino acid transporters (EAAT)- these are sodium dependent excitatory amino acid transports found in the pre-synaptic neuron

Question 13

Describe the process of degradation of glutamate, stating the enzymes involved

Answer 13

1)Glutamate broken down into Glutamine = via Glutamine synthatase
2)Glutamine is then moved out of the glial cells via SN1
3)Then transported into the neurons via SAT2

Question 14

where is system n transporter(SN1) located?

Answer 14

SN1 located in glial cells

Question 15

where is system A transporter 2 (SAT2) located

Answer 15

neurons

Question 16

what are the 2 broad families of neurotransmitter families?

Answer 16

1)Ligand-gated ion channels (ionotropic)= fast synaptic transmission
2)G-protein couples receptor (metabotropic)= slow synaptic transmission

Question 17

Name the 3 ionotropic receptors for glutamate and what molecules enter and leave via them.

Answer 17

1)AMPA receptor= influx of Na+, efflux of K+
2)NMDA receptor= influx of Na+ and ca2+, efflux of k+
3)Kainate receptor= influx of Na+, efflux of k+

Question 18

Describe the inotropic glutamate receptor structure of: AMPA

Answer 18

1) 4 subunit types (plus the alternate splice variants)= GluA1,GluA2,GluA3 and GluA4
2)Heterotetrameric= made of 2 subunits that are the same (have 4 subunits but there are 2 dimers of 1 subunit and 2 dimers of another)
3)Has 4 Orthosteric binding sites
4)For the ion channel to open- 2 orthosteric sites need to be occupied
5)The current increases as more binding sites get occupied

Question 19

within the AMPA receptors (including variants). what does the presence of GluA2 result in?

Answer 19

Prevents Ca2+ flow

Question 20

what does alternate splice variants of AMPA receptors mean?

Answer 20

Different versions or forms of the AMPA protein receptor made through the process of alternative splicing

Question 21

Describe the NMDA receptor

Answer 21

1)Can be made from 3 subunit types (plus their alternate splice variants)= GluN1 (or NR1), GluN2 (or NR), GluN3 (or NR3)
2)Hetero-tetrameric structure (from the 3 subunits 2 used as dimers= 4 subunits/proteins?)

Question 22

What affect does the use of GluN3 have on the NMDA receptor?

Answer 22

Inhibition

Question 23

Describe the structure of Kainate receptors

Answer 23

1) can be made from 5 subunits=GluK1 (or GluR5), GluK2 (or GuR6), GluK3 (GluR7),GluK4 (KA1), GluK5 (KA2)
2)Tetrameric structure (4 subunits)

Question 24

with the tetrameric structure of the kainite receptor describe the effect of using the different subunits.

Answer 24

1)GluK1-3 can form
homomers or
heteromers
2) GluK4 & 5 only
heteromers with GluK1-
3 subunits

Question 25

what are metabotropic receptors?

Answer 25

G-protein coupled receptors

Question 26

how many groups of metabotrpic receptors are there?

Answer 26

3

Question 27

how many subtypes can be found in GPCR’s and what are they?

Answer 27

1)8
2)mGlu1, mGlu2, mGlu3, mGlu4, mGlu5, mGlu6, mGlu7, mGlu8

Question 28

what subunits are found in which groups of metabroeceptors?

Answer 28

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

Question 29

What type of G protein are found in groups 1? what enzymes get activated as result and what end products do you get? their effects?

Answer 29

1)Group 1 = Gq coupled =PIP2 cleaved into IP3 and DAG- IP3 Receptor activation occurs on the ER= increase in Ca2+ release= long term potentiation, plasticity, transcription and translation.
cAMP phosphorylation phosphorylates the AMPA (found post synaptically)

Question 30

What type of G protein are found in groups 2 and 3? what enzymes get activated as result and what end products do you get? their effects?

Answer 30

1)Both are Gi/o coupled = coupled to adenyl cyclase, inhibiting it, which is negative and then down regulates the cAMP formation, thus inhibiting the NT release (found pre-synaptically)= act as autoreceptors

Question 31

Describe the actual structure/ appearance of the metaboreceptors group 1-3.

Answer 31

1)Venus flytrap domain
2)Cyteine rich domain
3)7 transmembrane proteins
4)c terminal domain (binds to alpha, beta and gamma subunit)
5)external N terminus, internal c terminus which connects to a lot of proteins

Question 32

in the metaboreceptors when there is binding to the c domain what happens?

Answer 32

alpha-beta and gamma activation

Question 33

The release of glutamate causes different ways of termination. what are the 3?

Answer 33

1)Diffusion away from the synapse
2)Reuptake from the excitatory amino acid transporters (EAATs)
3)Breakdown of glutamate itself

Question 34

excitatory nt result in what?

Answer 34

depolarisation

Question 35

what does the excitatory post-synaptic current (EPSC) represent?

Answer 35

The excitatory post-synaptic current (EPSC) represents the flow of ions, and change in current, across a post-synaptic membrane.

Question 36

What is the difference between the speeds at which EPSC formed from the 3 different ionotropic receptors?

Answer 36

1)NMDA and Kainate recepor= slower and last longer compared to AMPA receptors

Question 37

what is excitotoxicity?

Answer 37

Excitotoxicity is the pathological process by which excessive excitatory stimulation can lead to neuronal damage and death

Question 38

what does excess lvls of Ca2+ (excitotoxicity) result in?

Answer 38

Mitochondrial damage
Oxidative stress
Apoptosis

Question 39

what 2 conditions is excitotoxicity related to?

Answer 39

1)Alzheimer’s
2)Stroke

Question 40

in Alzheimers disease NMDA receptor over activation has been shown to be linked with glutamate mediated neurotoxicity and contribute to neuronal cell death. Describe the drug that can be used Alzheimers and how does it function?

Answer 40

Memantine is a low-affinity NMDA receptor
antagonist that blocks the NMDA receptor ion
channel to reduce glutamate mediated
neurotoxicity

Question 41

what is LTP?

Answer 41

Long-term potentiation (LTP) refers to the persistent strengthening
of a synapse based upon repeated patterns of activity.

Question 42

what is the mechanism of action of LTP?

Answer 42

Glutamate activates AMPA receptors, with
Na+ flowing into the post-synaptic neuron
and causing depolarisation
* NMDA receptors open, due to
depolarisation removing the voltage-gated
Mg2+ ion block
* Ca2+ ions enter the cell activate post-
synaptic protein kinases such as
calmodulin kinase II (CaMKII) and
protein kinase C (PKC)
* CaMKII and PKC trigger a series of reactions
that lead to the insertion of new AMPA
receptors into the post-synaptic
membrane
* AMPA receptors increase the post-synaptic
membranes sensitivity to glutamate and
increases ion channel conductance
* This underlies the initial phase of long-
term potentiation (LTP)