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Topics, trends & technologies in pharmacology > Ligand-gated ion channels > Flashcards

Ligand-gated ion channels Flashcards

1
Q

GABA-A receptor - properties

A

ligand-gated

permeable to Cl-

fast inhibition (= hyperpolarization)

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2
Q

GABA-B receptor - properties

A

GPCR

coupled to Ca2+ and K+ ion channels

slow inhibition

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3
Q

most common subunit combination

A

2 alpha, 2 beta and gamma

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4
Q

what do all alpha subunits have?

A

cys-cys pair in N-terminal extracellular domain

= essential for agonist binding

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5
Q

what occurs between TM3+4?

A

protein-protein interactions

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6
Q

what occurs at TM2?

A

pore forming domain

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7
Q

where does GABA bind to?

A

N terminal at interface of alpha/beta subunits

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8
Q

where does ACh bind to?

A

interface of 1 alpha/beta + alpha/delta subunits

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9
Q

TM2 domains

A

conserved leucine residue implicated in gating of ion channels

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10
Q

gate of ion channel

A

weak interactions between inner helices

hydrophobic gate rotates as GABA binds to open channel

rota of extracellular beta-sheets is transmitted to TM2 domain

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11
Q

how can affinity/efficacy be altered in ion channel?

A

having different alpha subunits

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12
Q

ion selectivity depends on…

A
  1. relative permeability
  2. pore size
  3. presence of charged groups lining pore
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13
Q

GABA-A + Gly receptors - type of channel?

A

anion channels

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14
Q

nAchR/5HT3 receptors - type of channel?

A

cation channels

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15
Q

what happens when GABA-A agonist binds?

A

induces conformational change

= increase in permeability of central pore to Cl-

= hyperpolarisation / inhibition

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16
Q

amino acid residues

A

Arg = +ve, basic

Asn, Ser, Thr = polar + no charge

Val, Leu, Ile = non-polar + no charge

glu = acidic, -ve

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17
Q

fast synaptic inhibition

A

low intracellular [Cl-]

GABA opens channel

inward -ve Cl- current

membrane hyperpolarizes

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18
Q

induced fit model

A

binding of agonist to receptor induces conformational change in region of ligand-binding site

propagates to pore region + causes opening of ion-conducting pore

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19
Q

allosteric model

A

receptor constantly undergoing spontaneous transitions between different conformers, which have different affinity for ligand

binding of agonist stabilizes channel in open state

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20
Q

determinants of IPSC kinetics

A
  1. lifetime of GABA at synapse (diffusions/reuptake mechanisms)
  2. post-synaptic GABA-A receptor composition
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21
Q

GABA-A receptor localization - alpha 1

A

high in cortex and cerebellum

22
Q

GABA-A receptor localization - alpha 2

A

restricted to hippocampus

23
Q

GABA-A receptor localization - alpha 3

A

high in cortex and hippocampus

24
Q

GABA-A receptor localization - alpha 4/5

A

restricted to hippocampus

25
Q

GABA-A receptor localization - alpha 6

A

restricted to cerebellum

26
Q

GABA-A receptor localization - gamma

A

important for trafficking Rs to cell surface

27
Q

synaptic GABA-A

A

high [GABA]

alpha 1,2,3,5 + gamma 2

BZ sensitive, anxiolytic + anticonvulsant

phasic activation + transient inhibition

28
Q

pre-synaptic GABA-A

A

low [GABA]

alpha 4,5,6 + delta

BZ insensitive, alcohol, anaesthetics + neurosteroids

persistent activation + tonic inhibition

29
Q

positive allosteric modulator

A

enhances agonist-induced action

30
Q

example of positive allosteric modulator

A

some BZ increase GABA induced Cl- channel opening by increasing efficacy of GABA (increases open frequency probability)

31
Q

negative allosteric modulator

A

reduces agonist-induced action

32
Q

example of negative allosteric modulator

A

barbiturates bind to different binding site and prolong lifetime of open state (even in absence of GABA)

overdose more likely to occur

33
Q

why are allosteric modulators used as a drug target over antagonists for LGIC?

A
  1. large repetoire for particular receptor
  2. binding not restricted to ligand binding site or ion pore
  3. orthosteric antagonists can cause unsurmountable blockade of receptor and obliterate response
34
Q

benzodiazepines (BZ)

A

= allosteric modulators

bind to interface between α/γ

core = benzene ring joined to 7-membered 1,4 diazepine ring

35
Q

how does changing the R groups affect BZ?

A

affects affinity and efficacy

36
Q

efficacy of BZ agonists

A

100% intrinsic efficacy

37
Q

positive effects of BZ

A

sedation

anxiolytic

hypnotic

anti-convulsant

38
Q

negative effects of BZ

A

memory loss

sedation

abuse potential

dependence

withdrawal symptoms

39
Q

which mutation affects BZ binding

A

α-His to α-Arg

abolished binding but didn’t affect receptor assembly or sensitivity to GABA

40
Q

which α-subunits contain His residue?

A

α1,2,3 + 5

41
Q

which α-subunits contain Arg residue?

A

α4,6 (resistant to BZ)

42
Q

which α-subunits are linked to sedative and amnesic effects?

A

α1

43
Q

which α-subunits are linked to anxiolytic effects?

A

α2,3

44
Q

light/dark choice test

A

conflict between approaching (wanting to explore) and avoiding bright light in new compartment

BZ increased time spent in bright light compartment

change in amino acid made BZ not work

45
Q

plus maze

A

2 sides open and 2 sides closed

after BZ - increased entry to open sides

mutation led to no response

46
Q

zolpidem

A

hypnotic

acts at BZ site (but not a BZ)

+ve allosteric modulator
-> increased amplitude
-> increased Cl- influx

47
Q

what mutation does zolipidem contain?

A

point mutation of Phe residue to Ile resiude in γ2 subunit

48
Q

alcohol

A

+ve allosteric modulator of GABA-A receptor

enhances GABA mediated tonic inhibition

49
Q

which subunits are sensitive to alcohol?

A

α1/α6

β

γ

50
Q

Ro-15-4513

A

blocks effect of alcohol at GABA-A receptor (antagonist)

decreases Cl- uptake

doesn’t block GABA-A, just enhancement in presence of alcohol

51
Q

which subunits does Ro-15-4513 have high affinity for?

A

α4/6

β

δ

Topics, trends & technologies in pharmacology (7 decks)

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