Ligand Gated Ion Channels

Question 1

what are the members of the LGIC family?

Answer 1

• 5-HT3
• GABAa + GABAc
• glycine
• glutamate

Question 2

where is nAChR located?

Answer 2

in periphery of NMJ

also found in CNS and spinal cord

Question 3

what is nAChR composed of?

Answer 3

5 transmembrane segments

2 alpha, beta, gamma, delta

are encoded by 4 diff genes

Question 4

the alpha polypeptide chains have …

Answer 4

binding sites for ACh

Question 5

what happens when 2 ACh molecules bind?

Answer 5

induce conformational change that opens channel

channel stays open for 1msec

Question 6

what are the 3 conformations of the ACh receptor?

Answer 6

• unoccupied + closed
• occupied + closed
• occupied + open

Question 7

what do clusters of negatively charged amino acids at either end of the pore help exclude?

Answer 7

negative ions

encourages pos ions of less than 0.65nm diameter to pass through

Question 8

what are the main ions that are able to pass through the pore?

Answer 8

Na+
K+
Ca2+

Question 9

what does a large influx of Na+ cause?

Answer 9

membrane depolarisation + skeletal muscle contraction

Question 10

what does prolonged contact of receptor with inc conc of ACh result in?

Answer 10

desensitisation of receptor

Question 11

what is the location, structure and signal transduction mechanism of the Nm receptor?

Answer 11

skeletal neuromuscular junction

pentameric

Na+ depolarising ion channel

Question 12

what is the location, structure and signal transduction mechanism of the Nn receptor?

Answer 12

post-synaptic cell bodies, dendrites

alpha and beta subunits only (as 2-alpha-3beta)

Na+ depolarising ion channel

Question 13

what are most neuronal nAChRs composed of?

Answer 13

alpha and beta subunits in ratio 2:3

Question 14

describe ligand-gated ion channel gating?

Answer 14

channels open/close in response to binding of signalling mol

e.g. ACh nicotinic receptors, GABAz receptors

Question 15

describe voltage-gated ion channel gating?

Answer 15

allow influx of ions into cell

found in neurones/cells

Question 16

what are the 3 subtypes of the GABA receptor?

Answer 16

• GABAa - ligand gated ion channel
• GABAb - G protein coupled receptors (exists as dimer)
• GABAc - ligand gated ion channel

Question 17

what are the GABAa and GABAc receptors linked to?

Answer 17

chloride ion channel

Question 18

how many subunits are there for the GABAa receptor?

Answer 18

there are 6 alpha, 3 beta and 3 gamma

in alpha2-beta2-gamma arrangement

Question 19

give examples of agents that are able to bind to GABA?

Answer 19

• neurosteroids
• anticonvulsants
• barbiturates
• convulsant - picrotoxin

Question 20

when GABA and BDZs act on their receptors, what do they do?

Answer 20

enhance binding of each other

BDZs cause conformational change - > modulates binding of GABA

GABA receptor changes from low affinity to high affinity

Cl- channel stays open

Question 21

give an example of a GABA agonist?

Answer 21

THIP (gaboxadol)

Question 22

give an example of a competitive agonist at GABAa?

Answer 22

bicuculline

Question 23

give examples of non-competitive agonists at GABAa?

Answer 23

picrotoxinin

TBPS

Question 24

what do GABA reuptake inhibitors do?

and also give an example of a reuptake inhibitor?

Answer 24

increase GABA levels at postsynaptic receptor

tiagabine (gabitril) -> derivative of nipecotic acid

is potent GABA reuptake inhibitor used as anticonvulsant

Question 25

what are the uses of barbiturates?

Answer 25

- hypnotics - used for severe insomnia in patients ALREADY taking barbiturates - sedatives - anticonvulsants - anaesthetics

Question 26

what are the thiobarbiturates?

Answer 26

derivatives of barbiturates contain sulphur mol in place of one oxygen mol

Question 27

what is thiopentone used as?

Answer 27

intravenous anaesthetic recovery = rapid few side effects

Question 28

what are the problems with barbiturates?

Answer 28

- patients develop tolerance - habit forming - therapeutic index = narrow - therapeutic dose v close to fatal dose - dangerous drugs -> used in suicide - interacts with alcohol

Question 29

give an example of BDZ receptor antagonist?

Answer 29

flumazenil prevents binding to BDZ but not GABAa

Question 30

what is flumazenil used for?

Answer 30

treatment of BDZ overdose

Question 31

what are the uses of BDZs?

Answer 31

- hypnotics | - anxiolytics - short term relief of severe anxiety

Question 32

what are the advantages of BDZs over barbiturates?

Answer 32

don't directly open Cl- channels not as lethal in overdose

Question 33

what effect does alcohol have?

Answer 33

- effect on GABAa receptors - opens Cl- channel - primary effect. in CNS as depressant - at low doses = stimulatory - inhib effects of ethanol suppress fear/anxiety

Question 34

effects of ethanol

Answer 34

- chronic use -> changes in brain + behaviour - enzyme responsible for metabolism = alcohol dehydrogenase - response in neurones is diminished

Question 35

what is the mechanism of action of alcohols?

Answer 35

- binds to multiple receptor sites on neurones - dissolves in lipid bilayer of membranes -> inc fluidity - binds to + enhances function of GABAa receptors

Question 36

L-glutamate

Answer 36

- major excitatory neurotransmitter in CNS - needed for normal brain function (lethal if too much) - receptors play vital role in synaptic plasticity + higher cognitive function - potential targets for therapies for CNS disorders

Question 37

ionotropic receptor subtypes consist of 4 subunits + are subdivided into 3 groups based on agonist selectivity what are they?

Answer 37

- NMDA (n methyl d-aspartate) receptors - AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic-acid) receptors - Kainic acid (KA) receptors

Question 38

what are the functions of NMDA receptors?

Answer 38

- synaptic plasticity - LTP (long term potentiation) learning/memory

Question 39

give the properties of NMDA properties?

Answer 39

- have high ca2+ permeability | - at single synapse - coexist with AMPA / kainate receptors

Question 40

unlike most receptors, what must bind to the receptor complex with glutamate to activate the receptor?

Answer 40

second agonist (co-agonist - glycine)

Question 41

NMDA receptors are tetrameric LGICs comprising...

Answer 41

- glycine binding GluN1 subunits | - glutamate binding GluN2A-2D + GluN3A-Bsubunits

Question 42

NMDA receptors are implicated in diseases such as….

Answer 42

- ischaemia/stroke (excessive glutamate) - parkinsons (pathways = overreactive) - Huntington's disease (disrupted ca2+ homeostasis --> excitotoxicity) - neuropathic pain

Question 43

AMPA receptors

Answer 43

- expressed in CNA | - tetramers of 4 subunits - GluA1-4

Question 44

what are AMPAkines?

Answer 44

drugs that can be useful in treating psychiatric + neurological diseases

Question 45

what do AMPAkines do?

Answer 45

help formation of LTP + can be used as memory enhancing drugs upregulate neurotrophins e.g. BDNF

Question 46

kainate receptors?

Answer 46

- more restricted distribution - tetrameric combinations of 5 subunits - GluK1-5 - involved in presynaptic regulation of neurotransmitter release - involved in excitatory imbalance - linked to epilepsy