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PHAL303 > Neurotransmitters and Receptors > Flashcards

Neurotransmitters and Receptors Flashcards

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
Q

5HT3

A

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

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26
Q

5HT4

A

Gs coupled GPCR located
in striatum/olfactory system/HPC

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27
Q

5HT5/6/7

A

Gs coupled GPCRs located
5: whole brain
6: striatum/cortex
7: hypothalamus/cortex

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28
Q

SERT

A

serotonin transport protein composed of 12 transmembrane domains
- transport is voltage dependent on Cl- and Na+ gradients
- targeted by SSRIs, TCAs, etc

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29
Q

Serotonin autoreceptor

A

5HTD

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30
Q

serotonin heteroreceptor

A

alpha-2 heteroreceptor

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31
Q

MAOa

A

Monoamine oxidase A
Degrades NA, 5HT, and DA but has highest affinity for 5HT

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32
Q

MAOb

A

Monoamine oxidase B
degrades DA and tyramine

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33
Q

Desensitisation of serotonin receptors

A

Desensitisation occurs rapidly through PKC-mediated phosphorylation, which is a calcium dependent process

Reversed via phosphatase action following ligand dissociation

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34
Q

Homeostatic responses to serotonergic activation

A

Desensitisation (rapid)
Internalisation (minutes to hours)
Downregulation (hours to days)

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35
Q

The monoamine hypothesis of depression

A

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
Q

Evidence against monoamine hypothesis of depression

A

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
Q

Development of anti-depressants

A

Relatively accidental
- first three were histamine based and created as an aesthetic
- TCAs developed as anti-psychotics
- SSRIs developed due to TCA toxicity

38
Q

Antidepressants

A
  • TCAs (nonselective inhibitors of monoamine uptake)
  • MAOIs (selective MAO inhibitors)
  • SSRIs (inhibit 5HT reuptake)
  • SNRIs (selective noradrenaline uptake inhibitors)
39
Q

Placebo effect of antidepressants

A

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
Q

MDMA

A

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
Q

GABA synthesis

A

conversion of glutamate to GABA vu glutamic acid decarboxylase (GAD65/GAD67)

42
Q

GABA breakdown

A

reuptake into synapse/glial cells via GAT
or
transamination via GABA transaminase (GABA-T)

43
Q

Percentage of GABA in brain synapses

A

30%

44
Q

What is the history of GABA?

A

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
Q

GABA mechanism of action

A

Binds to result in Cl- influx, which causes an IPSP

46
Q

GABAa structure

A

pentameric structure composed of three different distinct subtypes (a,b,y)

the combination determines the pharmacological characteristics of the receptor

47
Q

Most common composition of GABAa subunits

A

2a 2b 1y

48
Q

Where does GABA bind at GABAa receptors?

A

Between the alpha and beta subunits

49
Q

Where do BZDs bind at GABAa receptors

A

between the alpha and gamma subunits

50
Q

Distribution of GABAa

A

widespread through cortex and hippocampus

51
Q

GABAa antagonists

A

bicuculline (competitive)
picrotoxin (irreversible)

52
Q

GABAa agonists

A

muscimol and isoguvacine

53
Q

BZDs

A

Benzodiazepenes are positive allosteric modulators than bind between the alpha-gamma subunits of GABAa receptors and act to increase Cl- conductance

54
Q

Flumazenil

A

Antagonist at BZD site, thus acts to decrease Cl- conductance, and has an anxiogenic effect

55
Q

Overall effect of high GABA agonists

A

anxiolytic, sedative, hypnotic, muscle relaxant, anti-convulsant, amnesiac, dependency

56
Q

Overall effect of slight GABA agonists

A

anxiolysis

57
Q

Overall effect of slight GABA inverse agonists

A

anxiogenic

58
Q

Overall effect of GABA inverse agonists

A

anxiogenic and pro-convulsant

59
Q

EPM

A

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
Q

Light-dark test

A

An anxiety assay based on the conflict in rodents of innate light aversion and spontaneous exploratory activity

61
Q

Anaesthetic drugs that potentiate GABA response

A

Propofol and Etomidate

62
Q

Mutation that prevents anaesthetic drugs from potentiating GABA responses

A

S270W, a single mutation in the alpha subunit of GABAa

63
Q

Link between GABA and Alzheimers

A

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
Q

GABAb structure

A

A GPCR composed of 2 subunits
- B1a/B1b (ligand binding)
AND
- B2

65
Q

Effect of GABAb activation

A

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
Q

GABAb distribution

A

Present throughout the cortex, in both pre and post synaptic terminals

67
Q

GABAb antagonist

A

saclofen

68
Q

GABAb agonist

A

baclofen

69
Q

GABAc structure

A

Mono-pentameric structures composed of three receptor subunits p1, p2, and p3

70
Q

Location of r1 GABAc

A

retina

71
Q

Location of r2 GABAc

A

CNS

72
Q

GABAc receptors are considered a variant of GABAa despite only 30-38% AA specificity, but do not respond to…

A

bicuculline, baclofen, and BZDs

73
Q

Conditions associated with GABA

A
  • mental health
  • major depression
  • autism
  • huntington’s
  • epilepsy
  • parkinsons
74
Q

What are the three dopaminergic pathways in the brain?

A

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
Q

D1 receptor family mechanism

A

D1 & D5
- increased cAMP production
- K+ channel inhibition
- Ca2+ channel activation/inhibition
- enhancement of NMDA receptor response

76
Q

D2 receptor family mechanism

A

D2, D3, D4
- decrease cAMP production
- K+ channel activation = decreased post-synaptic excitability
- increased presynaptic inhibition via Ca2+ channels

77
Q

Dopamine receptors in striatum

A

D1, D2, D3, D4, D5 (all of them)

78
Q

Dopamine receptors in the cortex

A

D1, D2, D4

79
Q

Dopamine receptors in the hippocampus

A

D2, D3, D4, D5

80
Q

Dopamine receptors in the nucleus accumbens

A

D3

81
Q

Lifecycle of acetylcholine

A

Choline + Acetyl CoA
via choline acetyltransferase
= Acetylcholine + Coenzyme A

Acetylcholine
via Acetylcholine esterase
= Choline (recycled) + acetate (degraded)

82
Q

nAChR

A

composed of 5 subunits, each with four transmembrane domains and act to facilitate the passage of Na+, K+, and on occasion Ca2+.

83
Q

Homomeric nAChR

A

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
Q

Heteromeric nAChR

A

Heteromeric a4b2 receptors have high affinity for nicotine, are not blocked by a-bungarotoxin, and are moderately permeable to Ca2+.

85
Q

mAChR

A

muscarinic acetylcholine receptors are GPCRs and can be classified into 5 subtypes (M1-5) based on agonist/antagonist selectivity

86
Q

What are 3 main ACh pathways in the brain?

A
  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

PHAL303 (10 decks)

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