L8: Ligand-Gated Ion Channels

Question 1

Describe ligand-gated ion channels in terms of timescale, effector and coupling. Give examples

Answer 1

Timescale: milliseconds
Effector: channels
Coupling: direct
Example: nicotinic AChR; GABAa receptor; NMDA
mediator of fast synaptic transmission

Question 2

Why do Ligand-gated ion channels need to be tightly regulated?

Answer 2

• too much inhibition can result in loss of consciousness
• too much excitation can result in seizures

Question 3

What are the members of Cys Loop family of LGICs?

Answer 3

LGICs receptors of Cys Loop family:
- muscle nicotinic
- neuronal nicotinic
- GABAa
- Glycine
- 5-HT3

Question 4

On what receptors and where does ACh act?

Answer 4

• on muscle nicotinic in endplate
• on neuronal nicotinic in autonomic ganglia, CNS

Question 5

On what receptors and where does GABA act?

Answer 5

on GABAa receptors in CNS (brain)

Question 6

On what receptors and where does glycine act? Inhibitory or excitatory?

Answer 6

on glycine receptors in CNS (spinal cord, brainstem); inhibitory

Question 7

On what receptors and where does 5-HT act?

Answer 7

on 5-HT3 in CNS, periphery

Question 8

On what receptors and where does glutamate act?

Answer 8

• on NMDA receptors in CNS
• on AMPA receptors in CNS
• on kainate receptors in CNS

Question 9

On what receptors and where does ATP act?

Answer 9

on P2X receptors in CNS, periphery

Question 10

To which ions are muscle and neuronal nicotinic LGICs permeable, what’s their nature of action?

Answer 10

• muscle nicotinic to Na+, K+
• neuronal nicotinic Na+, K+, Ca2+
  they’re both excitatory (depolarisation)

Question 11

To which ions are GABAa and Glycine LGICs permeable, what’s their nature of action?

Answer 11

They’re both permeable to Cl- and are inhibitory

Question 12

To which ions are 5-HT3 LGICs permeable, what’s their nature of action?

Answer 12

To Na+, K+ and is excitatory (depolarisation)

Question 13

To which ions are NMDA, AMPA and kainate LGICs permeable, what’s their nature of action?

Answer 13

to Na+, K+, Ca2+, they’re all excitatory (depolarisation)

Question 14

Describe Cys-loop type LGICs and give examples

Answer 14

• pentameric assembly
• 4 TM domains
• long cys-loop
• TM2 lining the ion channel pore

examples: nAChR, GABAa, 5-HT3

Question 15

Describe Ionotropic glutamate type LGICs and give examples

Answer 15

• tetrameric assembly
• 3 TM domains
• hairpin loop

example: NMDA

Question 16

Describe P2X type LGICs and give examples

Answer 16

• trimeric assembly
• 2 TM domains

example: P2XR

Question 17

Describe Calcium release type LGICs and give examples

Answer 17

• tetrameric assembly
• 6 TM domains
• hairpin loop
  example: IP3R

Question 18

Describe nAChRs

Answer 18

• pentameric
• 4 transmembrane domains (alpha-helices)
• TM2 lines the ion channel pore
• acetylcholine binds only in between alpha-gamma and alpha-sigma regions
• forms Cys-loop
• homology between the same subunit across species is very high (50-90%)

Question 19

How many transmembrane domains do nAChRs constitute of?

Answer 19

4 transmembrane domains

Question 20

Which transmembrane domain lines the nAChR ion channel pore? What’s the charge of it?

Answer 20

TM2, negative charge, cationic channel

Question 21

In between which regions does ACh bind in nAChRs?

Answer 21

acetylcholine binds only in between alpha-gamma (alpha-epsillon in adults) and alpha-sigma regions

Question 22

In between which transmembrane domains is this large Cys loop of nAChRs located?

Answer 22

Large intracellular loop between TM3 and TM4

Question 23

What is the importance of the Cys loop in nAChRs?

Answer 23

Key component in terms of ligand binding

Question 24

Where are muscle type and neuronal type nAChRs located?

Answer 24

• muscle type: neuromuscular junction
• neuronal type: autonomic ganglia, synapses within the CNS

Question 25

What makes nicotinic receptors permeable to cations?

Answer 25

Ring of negative charge of TM2 line the ion channel pore which makes nicotinic receptors permeable to cations

Question 26

Which subunit and how does it change in nAChRs in fetal and adult?

Answer 26

gamma is fetal, epsillon is adult

Question 27

Describe GABAa receptors (number of subunits, number of TM domains)

Answer 27

• comprised of five subunits
• four transmembrane domains

Question 28

Where is GABA binding site on GABAaR?

Answer 28

Two binding sites between alpha and beta subunits

Question 29

What subunits are GABAaRs most commonly formed of?

Answer 29

2 alpha, 2 beta and 1 gamma

Question 30

What is the agonist for GABAaRs?

Answer 30

Selective GABAaRs agonist is muscimol

Question 31

What is the antagonist for GABAaRs?

Answer 31

Selective, competitive, reversible GABAaRs antagonist is bicuculline

Question 32

Which subunit do benzodiazepines act only on GABAa receptors?

Answer 32

Benzodiazepines act only on GABAa receptors that have gamma subunit

Question 33

Which are the prinicipal face subunits in GABAaRs?

Answer 33

Beta subunits are principal face subunits in GABAa receptors

Question 34

Which are the complementary subunits in GABAaRs?

Answer 34

Alpha subunits are complementary subunits in GABAa receptors