PSC2002/L15 Ligand Gated Channels

Question 1

What is the difference between ionotropic and metabotropic glutamate receptors?

Answer 1

Ionotropic causes transient opening, cation influx and excitatory current
Metabotropic have modulatory role in synaptic transmission

Question 2

What is the role of glutamate?

Answer 2

Principal excitatory neurotransmitter in vertebrate nervous system
Important roles in learning, memory, various disorders

Question 3

Name 2 disorders associated with glutamate.

Answer 3

Epilepsy
Schizophrenia
Excitotoxicity

Question 4

What are the 3 main classes of receptors?

Answer 4

AMPA, NMDA and kainate receptors

Question 5

What is the difference between, AMPA, NMDA and kainate receptors?

Answer 5

AMPA & NMDA artificial
Glutamate & kainate activate all 3
NMDA & AMPA are specific agonists
KARs named by exclusion (kainate agonist; no effect on AMPA or NMDA)

Question 6

Where is each ionotropic GluR (iGluR) found? (3)

Answer 6

AMPAR & NMDAR co-localised at synapses (fast transmission)
All can be synaptic & extrasynaptic
All can be pre-synaptic (autoreceptors) and post-synaptic

Question 7

Where are GluRs mainly localised?

Answer 7

Postsynaptic sites
Dendrites of postsynaptic cell

Question 8

Give an agonist of KAR, AMPAR and NMDAR. Which ions are they mainly permeable to?

Answer 8

Agonist glutamate
NMDAR - Ca2+
AMPAR & KAR - Na+

Question 9

Describe the structure of iGluRs.

Answer 9

Multimeric protein complexes of 4 subunits (tetramer)
GABA and nAChRs have 5 subunits (pentamer)

Question 10

Describe the structure of iGluR subunits.

Answer 10

3 transmembrane domains (TM1, TM3, TM4)
Re-entrant loop (TM2)

Question 11

Describe AMPAR subunits GluA1-4.

Answer 11

Approx. 900aa, 68-73% identity
Can undergo 2 modifications (alternative splicing, RNA editing)
Can form homomeric and heteromeric channels
In heteromeric channels, presence of edited GluA2 determines the I-V curve and the Ca2+ permeability

Question 12

Give 2 splice variants that affect receptor kinetics.

Answer 12

Deactivation - agonist unbinding leads to closure of channel, requiring removal of transmitter
Desensitisation - channel closes while agonist remains bound

Question 13

What is a key difference between glutamate and ACh binding.

Answer 13

With glutamate present, receptor still closes

Question 14

What is the difference between flip and flop in AMPA receptors?

Answer 14

Flip gives a sustained current
Flop gives a transient current

Question 15

What does subunit composition of AMPA-R affect?

Answer 15

Ca2+ permeability

Question 16

What is the relationship between P(Ca/Na) and relative abundance of GluA2?

Answer 16

Inversely proportional

Question 17

Where are GluA2 receptors edited?

Answer 17

At the Q/R site

Question 18

Describe editing at the Q/R site of AMPA receptors.

Answer 18

DNA of GluA2 codes for glutamine Q- swapped for arg R by editing of mRNA
+vely charged Arg renders channels containing Glu2 impermeable to Ca2+ (most but not all)
Implications for plasticity & toxicity

Question 19

Where are Ca2+ permeable AMPARs found?

Answer 19

On all Bergman glial cells
Some hippocampal neurons
Some auditory neurons

Question 20

What makes the GluA2 subunit impermeable to Ca2+?

Answer 20

Single aa in middle of transmembrane loop
Sticks to middle of pore and block relatively large Ca2+ ions

Question 21

What is the rate of desensitisation proportional to?

Answer 21

Subunit composition and flip/flop variant

Question 22

What modulates AMPAR trafficking and gating?

Answer 22

Auxiliary subunits

Question 23

Describe kainate receptors.

Answer 23

Large presynaptic presence
Lower conductance than other GluRs
May have ionotropic & metabotropic actions

Question 24

How was it found that kainate receptors may have combined ionotropic and metabotropic actions?

Answer 24

From pharmacological manipulation of 2nd messenger systems, supported by absence of effect in knockout animals
Block an effect of KAR activation by targeting 2nd messenger systems

Question 25

Describe the structure of NMDA receptors.

Answer 25

Glycine site Channel pore Glutamate site Zinc site Proton site

Question 26

What is required for NMDA function?

Answer 26

Glycine

Question 27

Describe long-term potentiation. (4)

Answer 27

Very strong stimulus to single pathway - initial activity starts to depolarise the cell Potentiation specific only to stimulated pathway Long lasting increase in strength of synaptic connections Fundamental mechanism for synaptic plasticity, thought to underlie learning and memory formation in the brain

Question 28

Describe the AP5 rat experiment and what was found.

Answer 28

Rats put in a tank of water with a platform Without AP5, swam around the platform With AP5, swam all around the tank AP5 impairs spatial memory

Question 29

Give 3 general functions of Ca2+.

Answer 29

Cell division Death Structure Motility Organelle motility Gene expression

Question 30

Give 3 neuronal functions of Ca2+.

Answer 30

Transduces electrical into chemical signals Axon and dendritic elaboration and retraction Synaptic vesicle retraction Synaptic plasticity

Question 31

Describe compartmentalisation of Ca2+ entry.

Answer 31

Ca2+ release into the presynaptic space required for vesicular release Ca2+ also enters through postsynaptic channels- important for changing synapse strength

Question 32

How are Ca2+ binding proteins localised?

Answer 32

Signal sequences or localisation signals that direct them to particular subcellular compartments

Question 33

Describe Ca2+ transients.

Answer 33

Location and shape important Message is interpreted by presence and sensitivity of local Ca2+ sensors

Question 34

Describe synaptic NMDA activation and the downstream events that occur after this. (5)

Answer 34

Synaptic NMDA activation CREB activation BDNF gene expression BDNF release TrkB phosphorylation

Question 35

What occurs after extrasynaptic NMDA activation? (2)

Answer 35

CREB inactivation (cAMP response element binding protein) Loss of mitochondrial potential