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PMCOL 371 > 8 - Ligand-gated > Flashcards

8 - Ligand-gated Flashcards

1
Q

Ligand-gated ion channel receptors (LGICs) mediate ____ responses

A

Ligand-gated ion channel receptors (LGICs) mediate fast synaptic responses

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2
Q

Some LGICs are ____-selective while others are ____-selective

A

Some LGICs are Anion-selective while others are Cation-selective

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3
Q

In LGIC’s the receptor and channel are:

A

a part of the same receptor complex

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4
Q

LGIC receptors are ____, ____ proteins

A

LGIC receptors are large, multisubunit proteins (oligomers)

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5
Q

What are three examples of LGICs

A
  • Peripheral nAChR (nicotinic receptors)
  • GABAA receptor
  • Glutamate receptors
    - NMDA, AMPA, Kainate
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6
Q

Function of LGICs

A
  • Mediate fast synaptic responses
  • Essential for rapid communication within nervous system
  • Activation can happen in submillisecond timescale
  • Always an increase in membrane conductance
  • Ions flow down their concentration gradient
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7
Q

Receptors ____ in continued presence of agonist

A

Receptors desensitize in continued presence of agonist

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8
Q

Transmitter action is ended with ____, ____ and/or ____ of transmitter

A

Transmitter action is ended with destruction, diffusion and/or reuptake of transmitter

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9
Q

Two reasons why nicotinic acetylcholine receptors (nAChR) are so well studied:

A
  • Abundant in the electric organs of the torpedo fish
  • Availability of a high affinity probe: the snake toxin alphabungarotoxin
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10
Q

The peripheral nAChR is a ____ of four ____ subunits

A

The peripheral nAChR is a pentamer of four homologous subunits (alpha2beta-gamma-delta)

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11
Q

The peripheral nAChR has ____ alpha subunits with a total of ___ subunits

A

The peripheral nAChR has 2 alpha subunits with a total of 5 subunits

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12
Q

Subunits of the peripheral nAChR form a ____ complex around the central ion ____

A

Subunits of the peripheral nAChR form a pseudosymmetric complex around the central ion pore

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13
Q

*Functional properties of nAChR
*
Release of ACh leads to binding to the ____ which has what effect on the channel

A

*Functional properties of nAChR
*
Release of ACh leads to binding to the nAChR which opens the nAChR within about 0.3msec

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14
Q

The nAChR is much more likely to open if what happens?

A

Positive Cooperativity: ACh molecules bind to each of the two binding sites

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15
Q

The nAChR channel is ____-selective with a diameter of _____

A

The nAChR channel is cation-selective with a diameter of 0.65nm

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16
Q

Synaptic transmission is normally terminated by the action of ____

A

Synaptic transmission is normally terminated by the action of acetylcholinesterase (AChE)

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17
Q

What happens to the nAChR in the continued presense of ACh?

A

The receptor becomes desensitized

Channel closes and the receptor adopts a conformation with a high affinity for ACh

Agonist must unbind and the receptor must rest to return to activatable conformation

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18
Q

What is the difference between muscle nAChRs in adults and embryos?

Subunits?

Conductance?

Burst duration?

A
  • Adult junctional receptor
    • alpha2-beta-epsilon-delta subunits
    • Large conductance (60ps)
    • Short burst duration
  • Embryonic and denervated
    • alpha2-beta-gamma-delta subunits
    • lower conductance (40ps)
    • Longer burst duration
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19
Q

Neuronal nAChRs

  • subunits
  • blocked by:
A
  • stoichiometry alphanbetam
  • blocked by k-bungarotoxin
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20
Q

How are chimeric receptors constructed?

A

By inserting the amino acid sequence of one receptor into the corresponding region of another

OR

by substituting subunits from other organisms (eg mouse vs torpedo)

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21
Q

What is possible if we characterise the properties of the chimera receptor?

A

By characterising the properties of the chimera it is possible to explore the functional importance of different parts of the protein or (as here) oligomer

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22
Q

____ subunits are important in conferring nAChR channel properties

A

delta subunits are important in conferring channel properties

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23
Q

Which receptor is the major inhibitory LGIC in the CNS?

A

GABAA

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24
Q

GABA causes ____ potential

A

fast inhibitory postsynaptic potential (IPSP)

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25
Q

What are two GABAA agonists?

A

GABA, muscimol

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26
Q

What is one antagonist to the GABAA receptor

A

Bicuculline

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27
Q

____ is a GABAa channel blocker

A

Picrotoxin (also blocks glycine receptor chlorine channel)

28
Q

Receptor binding similarity between GABAA and nAChR?

A

Both show positive cooperativity to agonist

29
Q

Which drugs have binding sites on the GABAA receptor?

A
  • Benzodiazepines
    • Tranquilizers, hypnotics, anxiolytic, antipanic and anticonvulsants
  • Barbiturates
  • Steroids
30
Q

Effect of benzos on GABAA

What does it require?

A
  • Increase affinity of GABAA for GABA
  • Increase frequency of channel opening
  • Potentiates GABA actions
  • Requires GABA agonist for its actions to be seen
31
Q

Effect of barbiturates on GABAA

A
  • Potentiate actions of GABA by shifting the dose-response curve to the left and increasing the maximum response
  • Increase channel open lifetime
32
Q

Effect of steroids on GABAA

A
  • Potentiate actions of GABA
  • Increase channel opening frequency and open lifetime
33
Q

Pentobarbital greatly increases both: (of GABAA)

A

Opening probability

Single channel conductance

34
Q

____ can open channel in the absence of GABA

A

barbiturates can open channel in the absence of GABA (unlike benzos)

35
Q

____ interface has binding site for GABA

A

beta-alpha interface has binding site for GABA

36
Q

Benzodiazepine binding site at ____ interface

A

Benzodiazepine binding site at alpha-beta interface

37
Q

Which subunit is necessary for expression of benzodiazepine binding site?

A

Gamma subunit

38
Q

Commonly, GABAA receptors in the brain consist of which subunits?

A

two alpha

two beta

one gamma

39
Q

____ is the major excitatory transmitter in the brain

A

glutamate is the major excitatory transmitter in the brain

40
Q

Glutamate receptors are ____ channels

A

Glutamate receptors are Cation channels (Na+ K+ Ca++)

41
Q

Glutamate receptor subtypes are defined by:

A

Specific agonists:

NMDA (activated by N-methyl-D-Aspartate)

non-NMDA (AMPA and Kainate receptors)

42
Q

Glutamate receptors mediate ____ excitation

A

Glutamate receptors mediate fast synaptic excitation

43
Q

Glutamate receptors are involved in ____ (important in learning and memory)

A

Glutamate receptors are involved in SYNAPTIC plasticity (important in learning and memory)

44
Q

What is synaptic plasticity?

A

Long-lasting, activity dependent changes in synaptic efficacy

45
Q

Excess glutamate transmission is involved in ____

A

Excess glutamate transmission is involved in neuronal cell death (excitotoxicity)

46
Q

When is excitotoxicity observed?

A

Following hypoxia, hypoglycemia, ischemia, epilepsy

47
Q

Excitotoxicity may be due to ____ influx through NMDA and non-NMDA receptors (glutamate receptors)

A

Excitotoxicity may be due to Ca++ influx through NMDA and non-NMDA receptors (glutamate receptors)

48
Q

Functions of AMPA receptors

A

AMPA receptors are a subtype of glutamate receptor

  • fast synaptic transmission
  • targets for memory-enhancing drugs
49
Q

Functions of Kainate receptors

A

Subtype of glutamate receptor

  • fast synaptic transmission
  • some presynaptic potentiating actions
50
Q

Functions of NMDA receptors?

A

subtype of glutamate receptor

  • Ca++ influx
    • trophic developmental actions
    • learning and memory
    • excitotoxicity
  • Slower than non-NMDA receptors
51
Q

Glutamate receptors have ____ transmembrane domains

A

Glutamate receptors have 3 transmembrane domains

Q/R site at M2

52
Q

GluR1-GluR4

  • high affinity for ____
  • form ____ channels
  • gated by ____ and ____
  • preferentially conduct ____, some conduct ____
    - Any channel containing _____ is Ca++ impermeable
  • Blocked by ____, ____, ____ and ____
A

GluR1-GluR4

  • high affinity for AMPA receptors
  • form homomeric channels
  • gated by AMPA and Kainate (and glutamate)
  • preferentially conduct Na+, some conduct Ca++
    • Any channel containing GluR2 is Ca++ impermeable
  • Blocked by CNQX, NBQX (AMPA and kainate), *GYKI53655 (AMPA-selective) *and kynurenic acid (non-selective glutamate)
53
Q

GluR5-GluR7

High affinity for ____

GluR5,6 form ____ channels

GluR7 does not form ____ channel

A

GluR5-GluR7

High affinity for kainate receptors

GluR5,6 form kainate-activated channels

GluR7 does not form homomeric channel

54
Q

KA1 and KA2 have high affinity for ____

A

KA1 and KA2 have high affinity for* KA binding proteins*

55
Q

AMPA receptors:

  • desensitize when activated by ____
  • Dont desensitize when activated by ____
A

AMPA receptors:

  • desensitize when activated by Glu or AMPA
    - Flip has small steady-state component
    - Flop desensitizes fully
  • Dont desensitize when activated by kainate
56
Q

KA receptors:

  • desensitize to ____ or ____
  • Homomeric don’t respond to ____
  • GluR6/KA1 heteromer responds, doesn’t desensitize to ____, desensitizes to _____
A

KA receptors:

  • desensitize to Glu or Kainate
  • Homomeric don’t respond to AMPA
  • GluR6/KA1 heteromer responds, doesn’t desensitize to AMPA, desensitizes to Kainate
57
Q

What are the three main classes of subunits for NMDA receptors?

A
  • NR1
  • NR2A-NR2D
  • NR3A&B
58
Q

NR1 subunits of NMDA receptors form ____ channels

A

NR1 subunits of NMDA receptors form homomeric channels

59
Q

NR2A-NR2D subunits of NMDA receptors form ____channels with ____

A

NR2A-NR2D subunits of NMDA receptors form heteromeric channels with NR1

Do NOT form channels on their own

60
Q

NR2 subunit isoform regulates ____ (NMDA receptors)

A

NR2 subunit isoform regulates channel properties (NMDA receptors)

61
Q

Which subunits of NMDA receptors have the glycine binding site?

A

NR3A&B

62
Q

Homomeric NR1 NMDA receptors are ____gated currents

A

Glu

63
Q

Heteromeric (NR1 & NR2 (or NR3)) NMDA receptors

  • Require ____ as co-agonist
  • ____-competitive antagonist
  • ____ channel blockers (noncompetitive)
  • High ____ permeability
A

Heteromeric (NR1 & NR2 (or NR3)) NMDA receptors

  • Require glycine as co-agonist
  • APV-competitive antagonist
  • channel blockers (noncompetitive)
  • High Ca++ permeability
  • Different NR2 subunits confer different properties
    - kinetic
    - voltage dependent Mg++ block
64
Q

Which NMDA subunit family is expressed throughout the brain

A

NR1

65
Q

NMDA receptors have a ____ current-voltage relationship that is ____-dependent

A

NMDA receptors have a non-linear current-voltage relationship that is Mg2+-dependent

66
Q

Why don’t NMDA receptors conduct well at negative potentials?

A

Mg2+ blocks the channel, even when opened by glutamate

67
Q

When does Mg2+ unblock the NMDA receptor pore?

A

When cell is More Depolarized

PMCOL 371 (18 decks)

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