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Amino acid transmitters Flashcards

ELM 1

1
Q

2 main amino acid transmitter families

A
  • excitatory
  • inhibitory
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2
Q

excitatory amino acids

A
  • glutamate
  • aspartate
  • N- acetylaspartyl glutamate
  • (glycine)
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3
Q

Inhibitory amino acid transmitters

A
  • GABA
  • Glycine (taurine?, β-alanine)
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4
Q

what is the main inhibitory neurotransmitter in the brain

A

GABA

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5
Q

main inhibitory neurotransmitter in the spinal cord

A

glycine (also in brain but not main one)

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6
Q

glutamate

A
  • distributed in CNS
  • most common excitatory transmitter
  • vesicular release
  • EAAT (excitatory amino acid transporters) mops up Glu into neurons and astrocytes
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7
Q

glutamate-glutamine cycle

A
  • SNARE proteins activated with calcium release glutamate into synapse
  • uptake back into pre-synaptic nerve terminal via EAAT
    OR
  • astrocyte also has EAAT, Glu is recycled into glutamine (Gln) and taken up by glutamine transporter into pre-synaptic nerve terminal
  • Gln metabolised back into glutamate by glutaminase
  • re-packaged into vesicles
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8
Q

what changes glutamine into glutamate

A

glutaminase

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9
Q

glutamate receptor families

A
  • ionotriopic
  • metabotropic
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10
Q

ionotropic glutamate receptors / iGluR and the 3 broad families

A
  • ligand gated ion channels
  • fast
  • 3 TMDs / lining between 1st and 2nd is a dip
  • AMPA (Quisqualate)
  • Kainate
  • NMDA
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11
Q

metabatropic glutamate receptors or mGluR and the 3 main families

A
  • Family C GPRs
  • always act as dimers
  • slower
  • tetrameter / 4 agonist binding sites
  • group 1: mGluR 1,5
  • group 2: mGluR 2,3
  • group 3: mGluR 4,6,7,8
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12
Q

AMPA receptors - iGluR

A
  • mediate fast synaptic transmission
  • fast EPSP
  • widely distributed in CNS
  • permeable to Na+, K+, some Ca2+ depending on sub-unit structure
  • 4 sub-units, each binds glutamate, needs 2 occupied to be activated
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13
Q

Kainate receptors - iGluR

A
  • found only in pre-synaptic terminals
  • fast EPSP
  • almost never permeable to Ca 2+ compared to AMPA
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14
Q

what AMPA sub units are highly permeable to calcium in the brain

A

GluA1,3,4

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15
Q

what AMPA sub-units are highly permeable to calcium in CNS

A

GluA1,3

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16
Q

what sub-unit on AMPA receptors means its impermeable to calcium

A

GluA2 - at position 607

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17
Q

NMDA receptors

A
  • highly permeable to Ca2+, - - blocked by Mg2+ at Resting membrane potential
  • need glycine (or D-serine) as a coagonist
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18
Q

what does the sub-unit GluN1 bind

A

glycine

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19
Q

what sub-unit binds glutamate

A

GluN2/3

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20
Q

what is co-agonism specific to

A

NMDA receptors
- we need glycine AND glutamate to get any response

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21
Q

NMDA receptor as a drug target

A
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22
Q

magnesium block of NMDAr

A

we need to depolarise the membrane so the Mg2+ block moves and we get ion influx

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23
Q

NMDA, AMPA, Kainate structure

A

tetramer

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24
Q

endogenous agonists of NMDA receptors for Aspertate

A

D- serine

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25
endogenous agonists of NMDA receptors for glutamate
glycine
26
summary of iGluR
- learn location, function and sub-unit types
27
metabotropic receptor family
- 8 different receptors mGluR 1-8 - members of Family C - 3 groups
28
Group 1 of mGluR
mGluR 1, mGluR 5 - somatodendritic location: cell bodies and dendrites - enhances NMDAr currents by inhibits K+ currents
29
Group 2 of mGluR
- 2 & 3 - mostly nerve terminal location: inhibitory auto-receptors and heteroreceptors
30
Group 3 of mGluR
- 4, 6, 7, 8 - nerve terminal location - inhibitory autoreceptors and heteroreceptors
31
Group 1 in treatments
- antagonist, can treat pain, Parkinsons or epilepsy
32
mGluR6
found only in the retina
33
normal transmission
- current flow induced by AMPA activation leads to loal depolarisation - transmits to soma ? - local depolarisation 'deinactivates' NMDA due to Ca influx - transmits to soma ! but - mGluR activation slows + increases depolarisation as can lift Mg block - synapse may become strengthened with repeated use (Long Term Potentiation)
34
which receptor type ONLY forms heterotetrameric complexes
NMDA receptors, need to bind both glycine AND glutamate to be activated - need GluN1 for glycine and GluN2 or 3 for glutamate
35
GABA
y- aminobutyric acid - widely distributed in CNS - vesicular release - transporter proteins for re-uptake into neurons and glia
36
what is GABA formed from
glutamate by glutamic acid decarboxylase (GAD)
37
2 types of GABA receptors
GABA-A : ionotropic GABA-B (C as subset) : metabotropic
38
GABAergic terminals
- GABA released via vesicular release - GAT1 takes GABA back to pre-synaptic nerve terminal - GAT2/3 takes GABA into astrocyte where it is metabolized into glutamine, which is taken to pre-synaptic terminal and converted to glutamate via glutaminase, and glutamate into GABA via glutamate decarboxylase (GAD)
39
GABAergic transmission
- ~20% of all CNS neurons are GABergic - usually short/local connections so common - some long projections - GABA in brain tissue not just located in synapse
40
long GABAergic projections
- striatum to substantia nigra/ globus pallidus
41
GABA-A receptors
- ligand gated chloride channels - produce inhibition - when GABA binds we have increased Cl- permeability
42
how do GABA-A receptors produce inhibition
- reversal potential for chloride (E-Cl) is close to RMP, so increase in chloride permeability (P-Cl) helps stablise MP close to RMP which inhibits the cell as any excitation is opposed by chloride
43
what do GABA-A receptors have
allosteric sites where other drugs can bind and either increase or decrease function of receptor
44
compounds that enhance GABA-A receptors function....
- sedatives - anxiolytics - anticonvulsants
45
compounds that decrease GABA-A receptors..
- convulsants - anxiogenics
46
GABA-A receptor sub-unit genes
- around 19 sub-units - 3 alpha - 3 beta - 3 gamma - delta - epsilon - phi - theta - rho
47
rho subunits
P1-3 GABA-C receptors - retinal expression
48
most GABA-A receptors
- pentamer - contain 3 types of sub-units - 2 alpha, 2 beta, gamma or delta
49
where is the main GABA-A binding sites
- formed at interfaces of beta and alpha subunits
50
what is the second GABA-A binding site and where is it
- benzodiazepine site - alpha and neighboring gamma (Y2 necessary)
51
extrasynaptic GABA-A receptors
- outside of synapses - responds to 'ambient' GABA: leaks out of synapses and uptake mechanisms - contain delta instead of gamma or a5 and y2 - insensitive to benxodiazepines - target of alcohol, neurosteroids, and general anaesthetics
52
GABA-B where are they found and what sub-units
- found pre- and post-synaptically - GABA-B1 and GABA-B2 (together as dimer)
53
what family are GABA-B receptors found and what do they do
- family C of GPCRs - operate as a dimer - inhibit CA++ channels - open K+ channels - inhibit AC via Gi
54
GABA-B1 vs B2
- B1: finds GABA - B2: doesn't bind GABA but interacts with G-protein
55
GABA-A vs GABA-B revision slide
56
glycine pharmacology as an inhibitory neuotransmitter
- high conc. in spinal cord (some in brain) - action at GlyR different from NMDA - transporter for reuptake and astrocytes
57
what kind of receptor is GlyR
cys-loop receptor
58
transporter for glycine re-uptake as an inhibitory neurotransmitter
- GlyT1 (astrocytes in CNS) - GlyT2 (SPINAL CORD)
59
sources of glycine
- diet - synthesis from metabolism of serine
60
glycine receptor structure - GlyR
- cys-loop - pentamer - 3 alpha, 2 beta sub-units in humans
61
the three different glycine alpha sub-units and where they are found
a1: spinal cord, brain a2: brain a3: brain
62
renshaw cells
- spinalcord interneurons - stimulated by collaterals from alpha motor neurons - inhibitory interneurons - antagonistic motor neurons
63
inhibitory internuerons - renshaw cells
release glycine onto motor neurons
64
antagonistic motor neurons - renshaw cells
negative feedback regulation of motor neurons
65
glycine receptor antagonist
strychnine - competitive - from a plant - renshaw cells cannot function
66
antagonist for glycine receptors
Strychnine
67
uses for glycine
potential to treat pain, epilepsy, hyperekplexia, alcoholism
68
GABA-A agonists
calming effect increased inhibitory transmission
69
muscimol
- principal psychoactive substance found in fly agaric mushrooms - agonist at GABA-A receptors
70
GABA is transported into presynaptic nerve terminals by which transporter
GAT1
71
GABA is transported into astrocytes by which transporter
GAT2
72
How many different glycine receptor α subunits are expressed by humans?
3 - (4 genes but alpha 4 is pseudogene and not expressed)
73
A spinal cord, glycinergic, inhibitory interneuron type is the:
renshaw cell
74
The GABAA receptor binding site for benzodiazepines is located at the interface of:
α and γ2 (necessary)
75
How many subunits do functional GABAB receptors contain?
2 - operate as dimers (same as mGluRs) - 1 GABAB1 and 1 GABAB2
76
what does the GABA-B1 subunit bind to
GABA
77
What does the GABA-B2 subunit bind to
interacts with G proteins
78
Lytico-bodig disease
- in the Chamorro people of Guam - traditionally food - or amyotrophic lateral sclerosis-parkinsonism-dementia
79
what is the lytico-bodig disease caused by
consumption of the cycad plants which contains BMAA toxin - in euope
80
what is BMAA
beta-methylamino-L-alanine - agonist at all 3 ionotropic glutamate receptors (NMDA, KAINATE, AMPA) - overactivation leads to excitotoxicity
81
how is excitotoxcicity caused
build up of calcium in neurons
82
where can BMAA also be found
in fruit bats concentrated in their tissues - cycad seads - example of bioaccumulation
83
how are cycads synthesising BMAA
- through cyanobacteria that live symbiotically in plants roots
84
Lathyrism
- due to consumption of legumes of the genus Lathyrus - eaten in times of famine
85
Lathyrus plant toxic ingredient
- glutamate analogue : OADP oxalyldiaminoproprionic acid - agonist at AMPA receptors (glutamate receptor) - similar symptoms to motor neuron disease, may result in paralysis
86
what binds quisqualate
AMPA receptors
87
what glutamate receptor is common in the CNS and activates around -70mv
AMPA
88
what glutamate receptor can be pre-synaptic
kainate
89
what receptor is formed from GluN subunits
NMDA
90
what receptor is formed from GluK subunits
kainate
91
what is a target of memantine
NMDA receptors

Drugs & the Brain (21 decks)

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