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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

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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
what site do AMPAr NAMs bind
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
26
what is UBP310
GluK1 antagonist
27
why is UBP310 so potent
thiophene ring favourable interaction with valine residue in GluK1 enhances binding activity
28
why is UBP310 specific
valine residues in GluK1 are replaced by leucing in AMPArs which is larger and impeded the antagonist binding
29
what is UBP161
potent gluk1 antagonist, much weaker at 2/3
30
what is UBP161s interaction
hydrogen bond of carboxylic acid group with serine residue on receptor
31
why is UBP161 weak at GluK3
serine residue is replaced by hydrophobic alanine so H bond lost
32
what do AMPA and KArs show with sustained activation by s-glutamate
rapid desensitisation
33
what does Concanavalin do
PAM - blocks desensitisation of Gluk1/2 containing but not homomeric GluK3 containing KARs
34
what does CTZ do
block GluA2 desensitisation
35
how does flip flop AMPAr occur
alternative splicing region results in 9-11 amino acid difference
36
what are Flop AMPAr characteristics
desensitises faster and recovers more slowly.
37
what is Flip AMPAr main characteristic
more sensitive to CTZ
38
where does flip flop occur
LBD, in extracellular peptide chain joining TMD3 and 4 (S2)
39
what conformational change occurs when glutamate binds to AMPArs
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
how are AMPARs desensitised
symmetry of arrangement of LBDS in tetramer change to match the ion channel in closed state
41
how does GluA2 flip show CTZ prevents desensitisation
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
what is CX614
PAM for GluA2
43
wher does CX614 bind
hinge region of dimer interface of GluA2 and stabilises the closed LBD conformation to slow deactivation
44
what can AMPAr PAMs be used for therapeutically
facilitate synaptic transmission in hippocampus to improve performance in animal models of learning and memory
45
what interacts with KAR to modify their properties
Neto 1 and 2
46
what interacts with AMPArs to modify their properties
TARPs
47
how does Neto1 KO affect KARs
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
what does TARP stand for
Transmembrane AMPA receptor regulatory proteins
49
what TARP was first discovered
stargazin - y2
50
what does y2 TARP KO cause
stargazing phenotype
51
what is y2 TARP needed for
functional expression of AMPARs in cereballer granule cells
52
what do TARPs help
trafficking AMPAr to cell surgace
53
how many families of subunits do NDMARs have
3
54
how many isoforms of GluN1 exist
8
55
how do isoforms of GluN1 exist
alternative splicing on a single gene
56
what is most common NMDAR assembly
2N1 and 2N2
57
what NMDAr does glycine activate
GluN1/3 tetramers when co expressed in xenopus oocytes
58
where does glycine bind on NMDARs
GluN1
59
where does glutamate bind on NMDArs
GluN2
60
at what voltage is Mg block removed in NDMARs
-35mv
61
what does NMDAR mediate
slow EPSP
62
is desensitisation more profound and faster with GluN2a or 2b
2A
63
do GluN2c or d containing NMDARs undergo desensitisation
no
64
name two compounds with high affinity for S1S2 domain of GluN1
glycine and d serine
65
name two competitive antagonists for GluN2 binding site
d-AP5, CPPene
66
where is GluN2A usually found
forebrain, cerebellum,, CA1
67
where is GluN2B usually found
medial striatum and CA1
68
where is GluN2C usually found
mainly in cerebellu,
69
where is GluN2D usually found
medial thalamus, hippocampus and spinal cord
70
what is NVP and what is its potency
GluN2 competitive antagonist. 2a ten fold over 2b
71
what is ifenprodil
selective GluN2B NAM binding to ATD dimer interface of GluN1/2B
72
what does ATD of NMDARs contribute to
control of ion channel open probability and deactivation rates
73
what is the major difference in x ray crystal structure of AMPARs and NMDARs
LBD-ATD region more compact in NMDARs
74
what is MPX-007
selective GluN2a NAM with a glycine con dependent effect (more inhibition at low conc)
75
why is MPX-007 selective
V783 switched to bulkier residues in GluN2B-d
76
What are auxillary proteins
TARPs - interact with AMPA receptors Neto 1 and Neto 2 - interact with KARs
77
What are possible therapeutic applications of AMPAkines?
*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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