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PHAL303 > Neurotransmitters and Receptors > Flashcards

Neurotransmitters and Receptors Flashcards

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1
Q

What is the history of glutamate?

A
  • Role as a neurotransmitter first suggest by Hayashi 1954 who injected glutamate into dogs and monkeys resulting in seizures
  • Found to depolarise neurons in cat spinal cord in 1950s
  • J.C watkins did a series of experiments in the 1970s that elucidated the ionotropic subtypes, showed the Mg2+ block in NMDA, and established L-glutamate as main neurotransmitter of CNS
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2
Q

Classes of glutamate receptors

A
  1. AMPA
  2. Kainate
  3. NMDA
    ^ all ionotropic
  4. mGluRs
    ^ metabotropic
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3
Q

EPSP

A

An electrical change (depolarisation) in the membrane of a postsynaptic neuron caused by the binding of an excitatory neurotransmitter from a presynaptic cell to a postsynaptic receptor, makes it more likely for a postsynaptic neuron to generate an action potential.

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4
Q

IPSP

A

An electrical change (hyperpolarisation) in the membrane of a postsynaptic neuron caused by the binding of an inhibitory neurotransmitter from a presynaptic cell to a postsynaptic receptor, makes it more difficult for a postsynaptic neuron to generate an action potential.

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5
Q

AP1 subunit

A

glutaminergic subunit that facilitates calcium permeability

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6
Q

Current dynamic of NMDA

A

Slow rise and slow decay

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7
Q

Current dynamic of AMPA

A

Rapid rise and rapid decay

Have varying pore size, depending on # glutamate occupying subunits (more glutamate, bigger pore, bigger EPSP)

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8
Q

Current dynamic of Kainate

A

Rapid rise and slow decay

Slow decay partially due to nearby AMPA receptor activation

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9
Q

NMDA antagonist

A

APV/AP5

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10
Q

AMPA antagonist

A

CQNX, GYKI (AMPA specific)

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11
Q

Kainate antagonist

A

CQNX

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12
Q

Shared features of AMPA and kainate

A

Agonists: glutamate, aspartate, AMPA, quisqualate, kainate
Antagonist: CQNX

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13
Q

Distribution of AMPA

A

AMPA is the most widely expressed glutamate receptor in the brain and is concentrated in:
- CA1
- thalamus
- TE
- cortex

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14
Q

Kainate distribution

A

Concentrated in
- CA3
- dentate gyrus
- cortex

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15
Q

Subunit arrangement of glutamate receptors

A

Different subunit arrangements present in a variety of compositions to give rise to receptors with widely different properties

These compositions can change over time, influenced by changes in condition

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16
Q

GluA2

A
  • AMPA without GluA2 or the unedited GluA2(Q) are permeable to calcium
  • AMPA with edited GluA2(R) are NOT permeable to calcium (majority)
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17
Q

Catecholamines

A

chemicals that have an amine group with either one (monoamine) or two (indolamine) rings

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18
Q

Peripheral action of serotonin

A

Serotonin is produced by enterochromaffin cells in the intestinal wall and platelets in the serum
= 90% of serotonin

Acts to regulate vascular tone

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19
Q

Central action of serotonin

A

Synthesised across brain, but primarily in the raphe nuclei

Acts as a neurotransmitter

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20
Q

Synthesis of serotonin

A

Tryptophan
- tryptophan hydroxylase
5-hydroxytryptophan
- dopa decarboxylase
Serotonin
- MAO

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21
Q

Marker used to identify serotonergic neurons

A

Tryptophan hydroxylase isoform 2

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22
Q

Diversity of serotonin receptors

A

The primordial serotonin receptor is over 750 million years old, and has given rise to the 7 key receptors that provide wide diversity

In addition to the core receptors there are transporter proteins and auto/heteroreceptors

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23
Q

5HT1

A

Gai coupled GPCR located throughout the CNS

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24
Q

5HT2

A

Gq coupled GPCR that acts to increase phospholipase C, and is located throughout the cortex

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25
5HT3
Cation channel expressed in cortical interneurons, the hypothalamus and the CTZ Required the 3A subunit for expression, and can be permeable to calcium depending on subunits expressed
26
5HT4
Gs coupled GPCR located in striatum/olfactory system/HPC
27
5HT5/6/7
Gs coupled GPCRs located 5: whole brain 6: striatum/cortex 7: hypothalamus/cortex
28
SERT
serotonin transport protein composed of 12 transmembrane domains - transport is voltage dependent on Cl- and Na+ gradients - targeted by SSRIs, TCAs, etc
29
Serotonin autoreceptor
5HTD
30
serotonin heteroreceptor
alpha-2 heteroreceptor
31
MAOa
Monoamine oxidase A Degrades NA, 5HT, and DA but has highest affinity for 5HT
32
MAOb
Monoamine oxidase B degrades DA and tyramine
33
Desensitisation of serotonin receptors
Desensitisation occurs rapidly through PKC-mediated phosphorylation, which is a calcium dependent process Reversed via phosphatase action following ligand dissociation
34
Homeostatic responses to serotonergic activation
Desensitisation (rapid) Internalisation (minutes to hours) Downregulation (hours to days)
35
The monoamine hypothesis of depression
Depression is due to a deficiency of noradrenaline and serotonin - some believe different forms are depression are more related to 5HT deficiency than NE or vice versa - most antidepressants act on NE/5HT however clinical effects take far longer than pharmacological effects
36
Evidence against monoamine hypothesis of depression
Individuals can have high serotonin and depression, or low serotonin and depression Antidepressants take ~5 weeks to exert clinical effects, yet their pharmacological effects occur rapidly
37
Development of anti-depressants
Relatively accidental - first three were histamine based and created as an aesthetic - TCAs developed as anti-psychotics - SSRIs developed due to TCA toxicity
38
Antidepressants
- TCAs (nonselective inhibitors of monoamine uptake) - MAOIs (selective MAO inhibitors) - SSRIs (inhibit 5HT reuptake) - SNRIs (selective noradrenaline uptake inhibitors)
39
Placebo effect of antidepressants
A significant portion of anti-depressant effects for mild/moderate depression are due to placebo Potentially due to effect of participating in a study including - reduced isolation - feeling important - taking initiative
40
MDMA
Reverses action of serotonin transporter, causing flood of serotonin at synapse (also affects DA/NA) Structurally similar to mescaline and amphetamine Neurotoxicity caused by primary metabolite MDA
41
GABA synthesis
conversion of glutamate to GABA vu glutamic acid decarboxylase (GAD65/GAD67)
42
GABA breakdown
reuptake into synapse/glial cells via GAT or transamination via GABA transaminase (GABA-T)
43
Percentage of GABA in brain synapses
30%
44
What is the history of GABA?
1800s: It was known as a metabolite of plants and micro-organisms 1900s: isolated as an amino acid in the mouse brain through paper chromatorgraphy 1950: Roberts and Frankel discover GABA in the human brain
45
GABA mechanism of action
Binds to result in Cl- influx, which causes an IPSP
46
GABAa structure
pentameric structure composed of three different distinct subtypes (a,b,y) the combination determines the pharmacological characteristics of the receptor
47
Most common composition of GABAa subunits
2a 2b 1y
48
Where does GABA bind at GABAa receptors?
Between the alpha and beta subunits
49
Where do BZDs bind at GABAa receptors
between the alpha and gamma subunits
50
Distribution of GABAa
widespread through cortex and hippocampus
51
GABAa antagonists
bicuculline (competitive) picrotoxin (irreversible)
52
GABAa agonists
muscimol and isoguvacine
53
BZDs
Benzodiazepenes are positive allosteric modulators than bind between the alpha-gamma subunits of GABAa receptors and act to increase Cl- conductance
54
Flumazenil
Antagonist at BZD site, thus acts to decrease Cl- conductance, and has an anxiogenic effect
55
Overall effect of high GABA agonists
anxiolytic, sedative, hypnotic, muscle relaxant, anti-convulsant, amnesiac, dependency
56
Overall effect of slight GABA agonists
anxiolysis
57
Overall effect of slight GABA inverse agonists
anxiogenic
58
Overall effect of GABA inverse agonists
anxiogenic and pro-convulsant
59
EPM
An anxiety assay that uses rodent's innate fear of open spaces and heights to model anxiolysis - time spent in open arms is used as an indication of anxiolysis - can only really model acute PTSD
60
Light-dark test
An anxiety assay based on the conflict in rodents of innate light aversion and spontaneous exploratory activity
61
Anaesthetic drugs that potentiate GABA response
Propofol and Etomidate
62
Mutation that prevents anaesthetic drugs from potentiating GABA responses
S270W, a single mutation in the alpha subunit of GABAa
63
Link between GABA and Alzheimers
In AD there is abnormal communication between GABAergic neurons and principal neurons This occurs at the same time as gliosis, toxic metabolite production, and plasticity impairement
64
GABAb structure
A GPCR composed of 2 subunits - B1a/B1b (ligand binding) AND - B2
65
Effect of GABAb activation
Ligand binding to the B1 subunit results in - inhibition of adenylate cyclase - pre-synaptic inhibition through reducing calcium influx - post-synaptic inhibition by increasing K+ permeability
66
GABAb distribution
Present throughout the cortex, in both pre and post synaptic terminals
67
GABAb antagonist
saclofen
68
GABAb agonist
baclofen
69
GABAc structure
Mono-pentameric structures composed of three receptor subunits p1, p2, and p3
70
Location of r1 GABAc
retina
71
Location of r2 GABAc
CNS
72
GABAc receptors are considered a variant of GABAa despite only 30-38% AA specificity, but do not respond to...
bicuculline, baclofen, and BZDs
73
Conditions associated with GABA
- mental health - major depression - autism - huntington's - epilepsy - parkinsons
74
What are the three dopaminergic pathways in the brain?
Mesolimbic: projections from the VTA to the NA and cortex Nigrostriatal: projections from the SNpc to the dorsal striatum Tuberoinfundibular: projections within the hypothalamus to control prolactin secretion
75
D1 receptor family mechanism
D1 & D5 - increased cAMP production - K+ channel inhibition - Ca2+ channel activation/inhibition - enhancement of NMDA receptor response
76
D2 receptor family mechanism
D2, D3, D4 - decrease cAMP production - K+ channel activation = decreased post-synaptic excitability - increased presynaptic inhibition via Ca2+ channels
77
Dopamine receptors in striatum
D1, D2, D3, D4, D5 (all of them)
78
Dopamine receptors in the cortex
D1, D2, D4
79
Dopamine receptors in the hippocampus
D2, D3, D4, D5
80
Dopamine receptors in the nucleus accumbens
D3
81
Lifecycle of acetylcholine
Choline + Acetyl CoA via choline acetyltransferase = Acetylcholine + Coenzyme A Acetylcholine via Acetylcholine esterase = Choline (recycled) + acetate (degraded)
82
nAChR
composed of 5 subunits, each with four transmembrane domains and act to facilitate the passage of Na+, K+, and on occasion Ca2+.
83
Homomeric nAChR
The homomeric a7 receptor is critically implicated in AD. These receptor have low affinity for nicotine, can be blocked by a-bungarotoxin, are permeable to Ca2+, and undergo rapid desensitisation.
84
Heteromeric nAChR
Heteromeric a4b2 receptors have high affinity for nicotine, are not blocked by a-bungarotoxin, and are moderately permeable to Ca2+.
85
mAChR
muscarinic acetylcholine receptors are GPCRs and can be classified into 5 subtypes (M1-5) based on agonist/antagonist selectivity
86
What are 3 main ACh pathways in the brain?
1. Septohippocampal pathway: modulates hippocampal neurons and the formation of new memories 2. Striatal interneurons: modulates the reinforcing properties of dopamine, and contributes to selection of behaviours 3. Nucleus basalis: radiate throughout the cortex, and are implicated in AD

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