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Serotonergic signalling (finished) Flashcards

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1
Q

How was serotonin discovered? - describe the experiment

(more of a context card)

A
  • Rapport & Page crystallised a compound (serotonin) in 1948 from 15L of blood serum in a 5 step process
  • Experiment = exposing artery rings of rat to compound, then read contractions of this muscle = Tension of rings increased dramatically
  • Named after ‘serum’ & ‘tonic’ meaning medicine = SEROTONIN
  • 1949, Rapport identified the molecular structure of serotonin as 5-HT
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2
Q

What does 5-HT stand for?

A

5-hydroxytryptamine

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3
Q

What is the structure of 5-HT?

A
  • Has an indole ring = 2 carbon rings
  • And an amine group

= an ‘indoleamine’ due to indole ring in the centre

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4
Q

Where is serotonin produced?

A
  • 90% produced in enterochromaffin cells (GI tract)
  • 2% in CNS
  • 8% in platelets
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5
Q

What molecules is serotonin similar to?

A

Hallucinogens/psychedelics

Specifically psilocybin

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6
Q

What is an example of something that contains hallucinogenic compounds?

A

Magic mushrooms contain psilocybin

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7
Q

What is another mushroom that has a similar effect but should not be confused with magic mushrooms + how is it different?

A

Fly agaric has muscimol as its primary psychoactive compound

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8
Q

Compare the effects of psilocybin with serotonin

A

similar psychoactive effects if concentrations high enough

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9
Q

When psilocybin gets into the body, what is it converted to?

A

Psilocin

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10
Q

What does psilocin act on?

A

serotonergic receptors

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11
Q

What are the functional effects of psilocybin similar to?

A

Lysergic acid diethylamide (LSD) = psychedelic drug
DMT , N-Dimethyltryptamine

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12
Q

Describe the effects of LSD

A

Effects typically include:
- Intensified thoughts, emotions and altered sensory perception.
- At sufficiently high dosages LSD manifests as primarily visual, auditory hallucinations.

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13
Q

What is DMT?

A

, N-Dimethyltryptamine is a substituted (5-hydroxy)-tryptamine that occurs in many plants and animals (= naturally occuring compound)- commonly used as a recreational drug & used for rituals in Southern American tribes

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14
Q

Name some plants that produce DMT

A

Phalaris, Delosperma, Acacia, Desmodium, Mimosa

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15
Q

What do DMT, LSD, sertonin and psilocybin all act on?

A

5-HT2A/C Receptor GPCR (Gq) to produce IP3 and DAG

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16
Q

What is this picture showing?

A

Label brain with radioligin which binds to seronergic receptor (shown in red)
+ psilocybin = reduction in signal- suggests psilocybin outcompetes serotonin

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17
Q

What are selective agonists + give one example

A

= molecules that bind and activate specific receptors e.g. psychedelics

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18
Q

What do selective agonists do?

A

Selective agonists stabilize a subset of receptor conformations (=different shapes) that selectively activates some but not all signaling pathways downstream

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19
Q

What this showing about selective agonists?

A

2 different drugs A and B acting on same receptor leading to activation of different pathways

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20
Q

Outline one hypothesis in the way in which psychedelics work

A

Induce different signalling routes downstream of activation of the same receptor
= biased agonism = activates receptors differentially = differing psychoactive effects between hallucinogenic and non-hallucinogenic compounds targeting the 5-HT2A receptor may be due to biased agonism.

Essentially, these compounds may activate different signaling pathways or induce different downstream effects upon binding to the receptor, leading to variations in their psychoactive effects

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21
Q

Where are serotonergic neurons located in the CNS and where do they project to?

A

2 main regions =

  • Rostral raphe nuclei in the brainstem- project to forebrain, thalamus and cerebellum
  • Caudal raphe nuclei- specifically raphe obscurus, pallidus and magnus – project to spinal cord and cerebellum.
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22
Q

What is the precursor for serotonin

A

tryptophan

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23
Q

Describe the synthesis of serotonin

A
  1. Tryptophan undergoes metabolism by tryptophan hydroxylase = 5-hydroxytryptophan
  2. this is further converted by L-aromatic amino acid decarboxylase into serotonin (5-HT)
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24
Q

What is the rate limiting step in the synthesis of serotonin?

A

The conversion of tryptophan to 5-hydroxytryptophan by tryptophan hydroxylase (=the rate limiting enzyme)

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25
Q

What does tryptophan hydroxylase require?

A

Enzyme requires tetrahydrobiopterin (BH4), NADPH and metal ion (iron or copper).

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26
Q

What does the amount of serotonin produced depend on?

A

The availability of tryptophan that crosses the blood brain barrier

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27
Q

Can tryptophan cross the blood brain barrier?

A

Yes- only free plasma tryptophan (unbound to albumin) crosses BBB

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28
Q

When crossing the blood brain barrier, what is tryptophan competing with?

A

Other neutral amino acids

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29
Q

What does increased cortisol do to tryptophan?

A

Plasma cortisol, which is increased in depression, decreases plasma free tryptophan concentrations: potential to trigger further depression- as reduces serotonin

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30
Q

What is the precursor for melatonin?

A

serotonin

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31
Q

Where is melatonin produced?

A

pineal gland

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32
Q

What enzymes are involved in the synthesis of melatonin?

A

5-HT N-acetyltransferase
5-hydroxyindole-O-methyltransferase

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33
Q

What is the main function of melatonin?

A

Regulate circadian activity of mammals

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34
Q

How is expression of enzymes that produce melatonin regulated?

A

Regulated in a circadian manner

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35
Q

What is the production of melatonin limited by?

A

production of melatonin is limited by the expression of enzymes

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36
Q

What does melatonin act on and where are they found?

A

Acts on melatonin receptors- predominantly MT1/2, MT3 (amphibia, birds)
- is found in the entire body including in the hypothalamus, hippocampus and other parts of the CNS

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37
Q

Describe the way in which metatonin works

A
  1. Melatonin binds to melatonin receptors (GPCR)
  2. MT1 receptors = Gi cascade- AC inhibition so reduces cAMP signalling
  3. MT2 receptors = Gq cascade- activates PLC and DAG signalling
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38
Q

What does the MT1 receptor induce downstream after activation?

A

Induces expression of protein called period = circadian activity protein

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39
Q

How does the activity of the 2 enzymes producing melatonin vary throughout the day and what effects this?

A
  • Melatonin levels in the pineal gland show circadian variations: following changes in N-acetyl transferase activity, increasing during the night (7-150fold) and decreasing during the day.
  • Light inhibits melatonin biosynthesis.
  • Melatonin controls sleep patterns and hormone rhythms.
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40
Q

What does dysfunction of melatonin result in?

A

Related to disease- has effects on several cascades within brain

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41
Q

Describe an example of melatonin dysfunction

A

Pineal gland degenerates = less enzymes present to produce melatonin

Induces oxidative stress
Can contribute to amyloid plaque
Tau pathology = hyper phosphorylation of tau protein

All implicated in alzheimers

42
Q

Outline an experiment that suggests decreased melatonin reduces the Abeta in mice

A

Amount of Abeta in brain of mice possessing mutation (Tg2576)
Treat mice with melatonin = reduction of Abeta (associated with alzheimers)

43
Q

(Same experiment) How does this effect the survival of the mice?

A

Untreated transgenic mice die over certain periods whereas melatonin treated mice survive much longer- supporting positive and protective role of melatonin in the brain

44
Q

What does melatonin do?

A

Has inhibitory action on expression of 2 proteins =
- BASE1 = beta-site amyloid precursor protein cleaving enzyme 1
- PSEN1= presenilin1

45
Q

explain what the BASE1 and PSEN1 are involved in

A

These 2 proteins are involved in the generation of amyloid plaques- as they favour b-secretase and y-secretase activity = drives amyloid precursor protein into amyloid plaque formation
= mutant proteins are associated with alzheimers

46
Q

How is serotonin metabolised?

A

2 step mechanism = cacscade of metabolism:
1. oxidation of serotonin amine group by monoamine oxidase (MAO-A) to produce 5-hydroxyindole acetaldehyde
2. oxidation by aldehyde dehydroxylase to 5-HIAA

47
Q

where is MAO-A located?

A

outer mitochondrial membrane

48
Q

What is 5-HIAA?

A

= inactive compound secreted by the kidneys

49
Q

Name 2 organisms in which MAOs are located

A

rodents
human

50
Q

What are the 2 forms of MAOs?

A

MAO-A
MAO-B

51
Q

Where are MAOs found?

A

both found in neurons and glial cells
MAO-A found in the liver
MAO-B found in platelets
- both specifically bound to mitochondrial membranes

52
Q

What is the % homology of the different forms of MAO?

A

70% = similar enzymes

53
Q

Describe how the different forms of MAO differ

A

Differ in substrate specificities
- MAO-A = main enzyme for serotonin, noradrenaline and adrenaline
- MAO-B = primarily for dopamine metabolism

54
Q

Name an example of a drug that targets MAO-A and what does it do?

A

Clorgyline selective MAO-A inhibitor (panic disorder and last line treatment for depression)- reduces metabolism increases serotonin

55
Q

describe the main form of 5-HT deactivation

A

Main form of deactivation of 5-HT is by serotonin transporter (SERT), removes serotonin from the synaptic cleft back into the synaptic terminals for reuse in vesicles.

56
Q

Where is SERT found?

A

SERT localised in midbrain raphe nuclues

57
Q

How does SERT work?

A
  1. SERT binds a Na+, then 5-HT, then a Cl-, and due to the membrane potential flips inside the cell freeing bound 5-HT into the cytoplasm.
  2. SERT then binds a K+ ion to flip back outside the cell membrane and return to its active state ready for more 5-HT reuptake (Symporter).
58
Q

What gene encodes SERT and which chromosome is it located on?

A

SLC6A4 gene on chromosome 17 encodes SERT.

59
Q

What are the 2 different polymorphisms of SERT?

A

The promoter region of the SLC6A4 gene contains apolymorphism and can have “short” or “long” (14 or 16) repeats.

60
Q

What is the difference between the polymorphisms of SERT?

A

The short 14 repeats variation leads to less transcriptionfor SLC6A4 and is associated with anxiety-relatedpersonality traits

61
Q

How many different serotonergic receptors are there and how many families do these come from?

A

Different genes code 14 distinct receptors in 7 different families (5-HT1 – 7)

62
Q

What are serotonergic receptors?

A

G-protein coupled receptors (GPCR) and one ion channel

63
Q

Across the different familes of serotonergic receptors, what is the homology?

A

40-50% amino acid homology

64
Q

Describe the general structure of 5-HT receptors

A

7 trans-membrane proteins
with three intracellular loops (1-3) and three extracellular loops (1-3)

65
Q

Why are mouse studies useful when studying serotonergic receptors?

A

Human and mice have closely related receptor genes

66
Q

which family is the 5-HT receptor that acts as an ion channel from?

A

3

67
Q

Name all the 5-HT receptors that act as ion channels

A

5-HT3A
5-HT3B
5-HT3C

68
Q

Name all of the 5-HT G protein coupled receptors (GPCR):

A
  • 5-HT 1A-F
  • 5-HT 4-7
  • 5-HT 2A-C
69
Q

Which 5-HT receptors are inhibitory?

A

1 and 5

70
Q

Which 5-HT receptors are excitatory?

A

2, 4, 6, 7

71
Q

What is the difference between Gs and Gi protein coupled receptors?

A

Gs = stimulate activity by increasing cAMP production
Gi = inhibit activity by inhibiting cAMP production

72
Q

Which 5-HT receptors are Gi receptors?

A

5-HT1
5-HT5

73
Q

What 5-HT receptors are Gs receptors?

A

4, 6 and 7

74
Q

What are Gq receptors?

A

Involved in different signalling pathway compared to Gi and Gs receptors
Instead they trigger activation of PLC which leads to production of IP3 and DAG

75
Q

which of the 5-HT g-protein coupled proteins are Gq receptors?

A

5-HT2

76
Q

Describe 5-HT1 receptors:

Type =

Mechanism =

Potential =

Pre or post?

A

Type = Gi protein coupled

Mechanism = Decreasing cellular levels of cAMP

Potential = Inhibitory

Pre and post synaptic

77
Q

Describe 5-HT2 receptors:

Type =

Mechanism =

Potential =

Pre or post?

A

Type = Gq/G11 protein coupled

Mechanism = Inc cellular levels of IP3 & DAG

Potential = Excitatory

Post synaptic

78
Q

Describe 5-HT3 receptors:

Type =

Mechanism =

Potential =

Pre or post?

A

Type = ligand gated Na+ & K+ cation channel

Mechanism = depolarising plasma membrane

Potential = Excitatory

Neither - an ion channel

79
Q

Describe 5-HT4 receptors:

Type =

Mechanism =

Potential =

Pre or post?

A

Type = Gs-protein coupled

Mechanism = inc cellular levels of cAMP

Potential = Excitatory

Post

(Same as 6 & 7)

80
Q

Describe 5-HT5 receptors:

Type =

Mechanism =

Potential =

Pre or post?

A

Type = Gi protein coupled

Mechanism = Dec cellular levels of cAMP

Potential = Inhibitory

Post

(Same as 1 but only on post)

81
Q

Describe 5-HT6 receptors:

Type =

Mechanism =

Potential =

Pre or post?

A

Type = Gs-protein coupled

Mechanism = inc cellular levels of cAMP

Potential = Excitatory

Post

(Same as 4 & 7)

82
Q

Describe 5-HT7 receptors:

Type =

Mechanism =

Potential =

Pre or post?

A

Type = Gs-protein coupled

Mechanism = inc cellular levels of cAMP

Potential = Excitatory

Post

(Same as 4 & 6)

83
Q

Where is 5-HT1A found & what is its role?

A
  • Found on dendrites, cell body & axon of the neuron
  • Acts as an auto receptor reducing 5-HT release
84
Q

Where is the 5-HT2 receptor found?

A

Found on the pre synaptic terminal

85
Q

What happens when a transmitter binds to 5-HT1A?

A
  • 1A is activated
  • Results in a decreased firing of synaptic potentials along the axon
  • 1A is found on cell body/denrites/axon
86
Q

What happens when a transmitter binds to 5-HT1B?

A
  • 1B is activated
  • There is dec serotonin release thru actions in presynaptic terminal
  • 1b is found on the presynaptic terminal
87
Q

name the cell types in the brain that contain serotonergic receptors

A
  • neurons- pre and post
  • astrocytes
  • Microglia
  • myelin sheath
88
Q

Summarise the whole process of serotonin signalling:

A

1 - Synthesis = serotonin is produced directly in the neuron

2 - Storage = VMAT2 releases serotonin into synaptic cleft

3 - Release = vesicle releases serotonin into synaptic cleft

4 - Activation = serotonin binds to receptor & initiates a signal to the cell body of the post-synaptic neuron

5 - Clearing = receptor clears. serotonin is taken up by either: presynaptic neuron, a logical cell or leaves cleft thru diffusion

6 - Re-uptake = after re-uptake, serotonin gets either reloaded into a vesicle/broken down

7 - Metabolism = MAO breaks down serotonin

89
Q

How does 5-HT relate to depression?

A

Reduced CNS 5-HT in depression reversed by selective serotonin reuptake inhibitors (SSRIs)

90
Q

What are hypothalamic neurones w neuroendocrine function regulated by?

Give an example

A

5-HT

e.g. cortisol by 5-HT2 receptors

91
Q

What does 5-HT release from the raphe nucleus regulate?

A
  • Sleep
  • Body temp
  • Food intake
  • Cognition
  • Mood
  • Vomiting
  • Pain perception
92
Q

How to migraines relate to 5-HT?

A

In a migraine there are chronically low levels of 5-HT –> due too disturbances in its synthesis

93
Q

How does 5-HT relate to epilepsy?

A

Alterations in 5-HT1A, 2C, 3 and 7 receptor subtypes in epilepsy

The binding capacity of 5-HT1A is lower

94
Q

What are SERT mutations associated with?

A

Anxiety-related disorders

95
Q

What region of the brain is associated with learning and memory?

A

hippocampus

96
Q

What is used to study serotonin signalling in humans and why?

A

Mouse studies used to study serotonin signalling in humans because they have similar brain structures

97
Q

Explain this table

A

Induced changes at the synapse =
- LTP = long-term potentiation = enhance activity post-stimulation
- LTD = long-term depression = suppress activity post-stimulation

Add different 5-HT4 agonists = alter outcome of plasticities- some are suppressing whereas some are enhancing

Take home message = Activation of 5-HT4 receptor has strong effects on plasticity within the hippocampus = impacts on learning and memory

98
Q

Describe an experiment (on mice) that shows action of 5-HT4 receptors within hippocampus

A

Induce stimulus via stimulation electrode
Record post-synaptic of neurons
Express amplification of activity over time following stimulus = either potentiate response or depress response

99
Q

How can you visualise the mouse experiment?

A

Can image brain of the mice e.g. (open scalp) over a period of time to see effects

100
Q

Describe an experiment used to test memory in mice + results

A

Put mice in water maze with a platform- if it remembers where it is it finds it very quickly

Then hide platform and measure time in which mouse takes to find platform- shorter time taken to find platform indicates better memory

Following activation of raphe nucleus- mice spend more time in area where platform was previously = serotonergic signalling improved memory

Disease in the brain (22 decks)

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