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PHA112 > Ligand Gated Ion Channels > Flashcards

Ligand Gated Ion Channels Flashcards

1
Q

what are the members of the LGIC family?

A
  • 5-HT3
  • GABAa + GABAc
  • glycine
  • glutamate
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2
Q

where is nAChR located?

A

in periphery of NMJ

also found in CNS and spinal cord

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3
Q

what is nAChR composed of?

A

5 transmembrane segments

2 alpha, beta, gamma, delta

are encoded by 4 diff genes

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4
Q

the alpha polypeptide chains have …

A

binding sites for ACh

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5
Q

what happens when 2 ACh molecules bind?

A

induce conformational change that opens channel

channel stays open for 1msec

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6
Q

what are the 3 conformations of the ACh receptor?

A
  • unoccupied + closed
  • occupied + closed
  • occupied + open
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7
Q

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

A

negative ions

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

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8
Q

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

A

Na+
K+
Ca2+

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9
Q

what does a large influx of Na+ cause?

A

membrane depolarisation + skeletal muscle contraction

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10
Q

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

A

desensitisation of receptor

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11
Q

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

A

skeletal neuromuscular junction

pentameric

Na+ depolarising ion channel

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12
Q

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

A

post-synaptic cell bodies, dendrites

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

Na+ depolarising ion channel

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13
Q

what are most neuronal nAChRs composed of?

A

alpha and beta subunits in ratio 2:3

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14
Q

describe ligand-gated ion channel gating?

A

channels open/close in response to binding of signalling mol

e.g. ACh nicotinic receptors, GABAz receptors

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15
Q

describe voltage-gated ion channel gating?

A

allow influx of ions into cell

found in neurones/cells

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16
Q

what are the 3 subtypes of the GABA receptor?

A
  • GABAa - ligand gated ion channel
  • GABAb - G protein coupled receptors (exists as dimer)
  • GABAc - ligand gated ion channel
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17
Q

what are the GABAa and GABAc receptors linked to?

A

chloride ion channel

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18
Q

how many subunits are there for the GABAa receptor?

A

there are 6 alpha, 3 beta and 3 gamma

in alpha2-beta2-gamma arrangement

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19
Q

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

A
  • neurosteroids
  • anticonvulsants
  • barbiturates
  • convulsant - picrotoxin
20
Q

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

A

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

21
Q

give an example of a GABA agonist?

A

THIP (gaboxadol)

22
Q

give an example of a competitive agonist at GABAa?

A

bicuculline

23
Q

give examples of non-competitive agonists at GABAa?

A

picrotoxinin

TBPS

24
Q

what do GABA reuptake inhibitors do?

and also give an example of a reuptake inhibitor?

A

increase GABA levels at postsynaptic receptor

tiagabine (gabitril) -> derivative of nipecotic acid

is potent GABA reuptake inhibitor used as anticonvulsant

25
Q

what are the uses of barbiturates?

A
  • hypnotics - used for severe insomnia in patients ALREADY taking barbiturates
  • sedatives
  • anticonvulsants
  • anaesthetics
26
Q

what are the thiobarbiturates?

A

derivatives of barbiturates

contain sulphur mol in place of one oxygen mol

27
Q

what is thiopentone used as?

A

intravenous anaesthetic

recovery = rapid
few side effects

28
Q

what are the problems with barbiturates?

A
  • patients develop tolerance
  • habit forming
  • therapeutic index = narrow
  • therapeutic dose v close to fatal dose
  • dangerous drugs -> used in suicide
  • interacts with alcohol
29
Q

give an example of BDZ receptor antagonist?

A

flumazenil

prevents binding to BDZ but not GABAa

30
Q

what is flumazenil used for?

A

treatment of BDZ overdose

31
Q

what are the uses of BDZs?

A
  • hypnotics

- anxiolytics - short term relief of severe anxiety

32
Q

what are the advantages of BDZs over barbiturates?

A

don’t directly open Cl- channels

not as lethal in overdose

33
Q

what effect does alcohol have?

A
  • effect on GABAa receptors - opens Cl- channel
  • primary effect. in CNS as depressant
  • at low doses = stimulatory
  • inhib effects of ethanol suppress fear/anxiety
34
Q

effects of ethanol

A
  • chronic use -> changes in brain + behaviour
  • enzyme responsible for metabolism = alcohol dehydrogenase
  • response in neurones is diminished
35
Q

what is the mechanism of action of alcohols?

A
  • binds to multiple receptor sites on neurones
  • dissolves in lipid bilayer of membranes -> inc fluidity
  • binds to + enhances function of GABAa receptors
36
Q

L-glutamate

A
  • 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
37
Q

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

what are they?

A
  • NMDA (n methyl d-aspartate) receptors
  • AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic-acid) receptors
  • Kainic acid (KA) receptors
38
Q

what are the functions of NMDA receptors?

A
  • synaptic plasticity
  • LTP (long term potentiation)
    learning/memory
39
Q

give the properties of NMDA properties?

A
  • have high ca2+ permeability

- at single synapse - coexist with AMPA / kainate receptors

40
Q

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

A

second agonist (co-agonist - glycine)

41
Q

NMDA receptors are tetrameric LGICs comprising…

A
  • glycine binding GluN1 subunits

- glutamate binding GluN2A-2D + GluN3A-Bsubunits

42
Q

NMDA receptors are implicated in diseases such as….

A
  • ischaemia/stroke (excessive glutamate)
  • parkinsons (pathways = overreactive)
  • Huntington’s disease (disrupted ca2+ homeostasis –> excitotoxicity)
  • neuropathic pain
43
Q

AMPA receptors

A
  • expressed in CNA

- tetramers of 4 subunits - GluA1-4

44
Q

what are AMPAkines?

A

drugs that can be useful in treating psychiatric + neurological diseases

45
Q

what do AMPAkines do?

A

help formation of LTP + can be used as memory enhancing drugs

upregulate neurotrophins e.g. BDNF

46
Q

kainate receptors?

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

PHA112 (37 decks)

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