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Pharmacology of the nervous system > structure and pharmacology of AMPA and kainate receptors > Flashcards

structure and pharmacology of AMPA and kainate receptors Flashcards

1
Q

what is VGLUT

A

transporter transfering cytosolic glutamate into vesicles

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2
Q

how is glutamate released

A

Ca2 dependent via VDCC

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3
Q

what type of proteins does glutamate target

A

ionotropic and metabotropic receptors

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4
Q

how is glutamate removed from synapse

A

glut transporters on pre and post nerve terminals, and astrocytres (EAAT1/2)

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5
Q

what is the basic AMPAr subunit composition

A

homomers or heteromers from GluA1-4

2xA1, 2xA2 most common

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6
Q

what is the AMPAr LBD comprised of

A

s1 and s2

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7
Q

what ions flow through AMPArs

A

K in, Na out, sometimes Ca

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8
Q

what affects AMPAr Ca permeability

A

RNA editing changing re entrant loop on GluA2 arginine at aa607 to glutamine

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9
Q

what were the first non selective, competitive AMPA/kainate antagonists

A

quinoxalinedione derivatives

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10
Q

what is CQNX mech

A

AMPA kainate and NMDA antagonist

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11
Q

what is NBQX

A

AMPA antagonist selective

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12
Q

what antagonises unedited GluA2

A

IEM_1460

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13
Q

What does philanthotoxin do

A

blocks edited GluA2 by pore blocking

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14
Q

what is the subunit composition of Kainate Rs

A

tetramers - GluK1-5

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15
Q

what subunits have low or high affinity of kainate

A

Gluk1-3 low, GluK4-5 high

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16
Q

What is different about homomeric GluK4/5 receptors

A

4/5 have RXR retention motif in c terminal tail so retained in endoplasmic reticulum and not surface expressed

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17
Q

what do kainate receptors do in CA1

A

presynaptic receptors that depolarise axon terminals and depress glutamate AMPAr transmission via inactivation of VGCC

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18
Q

what response do kainate receptors give in CA3

A

trains of stimulations trigger slow postsynaptic kainate response

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19
Q

what is structure of ATD in ionotropic glutamate receptors

A

clamshell with low sequence homology with bacterial periplasmic proteins and mGluRs.

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20
Q

what is ATD of ionotropic glutamate receptors involved in

A

receptor assembly and trafficking

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21
Q

what is structure of LBDin ionotropic glutamate receptors

A

clamshell

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22
Q

how do antagonists interact with LBD of iGluRs

A

wedge clamshell of s1 and s2 open so pore is shut

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23
Q

what is perampanel

A

anticonvulsant activity for partial seizures via AMPAr NAMs

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24
Q

what is perampanel or GYKIs mechanism

A

bind in TMD adjacent to peptide linker connecting TMD to LBD

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25
Q

what site do AMPAr NAMs bind

A

site formed by pre M1, M3 and M4 in each subunit. Also to a residue in M3 of adjacent subunit preventing movement of TM segments that is necessary for pore opening

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26
Q

what is UBP310

A

GluK1 antagonist

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27
Q

why is UBP310 so potent

A

thiophene ring favourable interaction with valine residue in GluK1 enhances binding activity

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28
Q

why is UBP310 specific

A

valine residues in GluK1 are replaced by leucing in AMPArs which is larger and impeded the antagonist binding

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29
Q

what is UBP161

A

potent gluk1 antagonist, much weaker at 2/3

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30
Q

what is UBP161s interaction

A

hydrogen bond of carboxylic acid group with serine residue on receptor

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31
Q

why is UBP161 weak at GluK3

A

serine residue is replaced by hydrophobic alanine so H bond lost

32
Q

what do AMPA and KArs show with sustained activation by s-glutamate

A

rapid desensitisation

33
Q

what does Concanavalin do

A

PAM - blocks desensitisation of Gluk1/2 containing but not homomeric GluK3 containing KARs

34
Q

what does CTZ do

A

block GluA2 desensitisation

35
Q

how does flip flop AMPAr occur

A

alternative splicing region results in 9-11 amino acid difference

36
Q

what are Flop AMPAr characteristics

A

desensitises faster and recovers more slowly.

37
Q

what is Flip AMPAr main characteristic

A

more sensitive to CTZ

38
Q

where does flip flop occur

A

LBD, in extracellular peptide chain joining TMD3 and 4 (S2)

39
Q

what conformational change occurs when glutamate binds to AMPArs

A

LBD closes and a corkscrew rotation opens the channel. upper lobes of LBDs pull down the ATDs, lower lobes of LBD exert lateral and upward pressure to force the ion channel open

40
Q

how are AMPARs desensitised

A

symmetry of arrangement of LBDS in tetramer change to match the ion channel in closed state

41
Q

how does GluA2 flip show CTZ prevents desensitisation

A

2 ctz bind in LBD dimer interface between two adjacent GluA2 subunits. each molecule spans the interface and stabilises it preventing conformational change to desensitisation

42
Q

what is CX614

A

PAM for GluA2

43
Q

wher does CX614 bind

A

hinge region of dimer interface of GluA2 and stabilises the closed LBD conformation to slow deactivation

44
Q

what can AMPAr PAMs be used for therapeutically

A

facilitate synaptic transmission in hippocampus to improve performance in animal models of learning and memory

45
Q

what interacts with KAR to modify their properties

A

Neto 1 and 2

46
Q

what interacts with AMPArs to modify their properties

A

TARPs

47
Q

how does Neto1 KO affect KARs

A

in mossy fibre → CA3 synapse, synaptic component loses slow kinetic profile (so it more resembles AMPAR response)

KO Neto1 means desensitisation occurs more quickly

48
Q

what does TARP stand for

A

Transmembrane AMPA receptor regulatory proteins

49
Q

what TARP was first discovered

A

stargazin - y2

50
Q

what does y2 TARP KO cause

A

stargazing phenotype

51
Q

what is y2 TARP needed for

A

functional expression of AMPARs in cereballer granule cells

52
Q

what do TARPs help

A

trafficking AMPAr to cell surgace

53
Q

how many families of subunits do NDMARs have

A

3

54
Q

how many isoforms of GluN1 exist

A

8

55
Q

how do isoforms of GluN1 exist

A

alternative splicing on a single gene

56
Q

what is most common NMDAR assembly

A

2N1 and 2N2

57
Q

what NMDAr does glycine activate

A

GluN1/3 tetramers when co expressed in xenopus oocytes

58
Q

where does glycine bind on NMDARs

A

GluN1

59
Q

where does glutamate bind on NMDArs

A

GluN2

60
Q

at what voltage is Mg block removed in NDMARs

A

-35mv

61
Q

what does NMDAR mediate

A

slow EPSP

62
Q

is desensitisation more profound and faster with GluN2a or 2b

A

2A

63
Q

do GluN2c or d containing NMDARs undergo desensitisation

A

no

64
Q

name two compounds with high affinity for S1S2 domain of GluN1

A

glycine and d serine

65
Q

name two competitive antagonists for GluN2 binding site

A

d-AP5, CPPene

66
Q

where is GluN2A usually found

A

forebrain, cerebellum,, CA1

67
Q

where is GluN2B usually found

A

medial striatum and CA1

68
Q

where is GluN2C usually found

A

mainly in cerebellu,

69
Q

where is GluN2D usually found

A

medial thalamus, hippocampus and spinal cord

70
Q

what is NVP and what is its potency

A

GluN2 competitive antagonist. 2a ten fold over 2b

71
Q

what is ifenprodil

A

selective GluN2B NAM binding to ATD dimer interface of GluN1/2B

72
Q

what does ATD of NMDARs contribute to

A

control of ion channel open probability and deactivation rates

73
Q

what is the major difference in x ray crystal structure of AMPARs and NMDARs

A

LBD-ATD region more compact in NMDARs

74
Q

what is MPX-007

A

selective GluN2a NAM with a glycine con dependent effect (more inhibition at low conc)

75
Q

why is MPX-007 selective

A

V783 switched to bulkier residues in GluN2B-d

76
Q

What are auxillary proteins

A

TARPs - interact with AMPA receptors

Neto 1 and Neto 2 - interact with KARs

77
Q

What are possible therapeutic applications of AMPAkines?

A

*Facilitate synaptic transmission in hippocampus - improve animal models of learning and memory
(subset = nootropic agents: ‘smart drugs’)

  • Promising results in treating cognitive deficits in Parkinson’s, AD and schizophrenia
  • Sleep-deprived healthy volunteers - improved performance in tests of memory, alertness, reaction time and enhanced problem solving ability
  • Clinical trails: prevention of opiate-induced resp depression without affecting analgesia
  • Sleep apnoea: phase III trials?
  • Depression: rapid onset treatment in animal models (increase BDNF)

Pharmacology of the nervous system (9 decks)

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