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Drugs and the Brain > Transmitters > Flashcards

Transmitters Flashcards

1
Q

What are the 2 Amino Acid transmitter families?

A

Excitatory

Inhibitory

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2
Q

Give examples of Excitatory Amino Acid transmitters (4)

A
  • Glutamate
  • Aspartate
  • N-acetylaspartyl glutamate
  • (Glycine)
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3
Q

Give examples of inhibitory Amino Acid transmitters (4)

A
  • GABA
  • Glycine
  • Taurine?
  • beta-alanine?
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4
Q

When was GABA recognised as a neurotransmitter?

A

1950-1970

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5
Q

When was Glycine recognised as a neurotransmitter?

A

1970-1980

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6
Q

When was glutamate recognised as a neurotransmitter?

A

1980s

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7
Q

Why did early research find it hard to believe that GABA, Glycine and glutamate were involved in signalling?

A
  • Because they are such ubiquitous molecules
  • The body has tightly controlled systems for keeping down the extracellular concentration of these molecules
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8
Q

How is Glutamate linked to GABA through metabolism?

A
  • Glutamate de-carboxylate cleaves he carboxylic acid group from glutamate to form GABA
  • Also
  • The GABA amino acid group can be used to make glutamate again
  • The two interconvert
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9
Q

How does Aspartate arise from amino acid metabolism?

A

GABA, Glutamate, Glycine feed into the Krebbs cycle

This leads to the production of Aspartate

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10
Q

Which amino acids transmitters are interconnected in metabolism?

A

GABA <—-> glutamate

glutamate—-> Glycine

All three—-> Aspartate

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11
Q

What is the most common excitatory amino acid transmitter?

A

Glutamate

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12
Q

How is glutamate released throughout the nervous system?

A

Vesicular release involving SNARE proteins and transporter proteins

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13
Q

What does EAAT do?

A
  • Mops up glutamate into neurons and astrocytes
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14
Q

Describe step-by-step the glutamate-glutamine cycle.

A
  1. vesicular release of glutamate into the synaptic cleft via SNARE function and calcium
  2. Glutamate acts on a receptor channel
  3. Signalling is terminated
  4. EAAT acts by taking up the glutamate into the presynaptic nerve terminal and an astrocyte
  5. In the presynaptic terminal, the glutamate is repackaged and ready for release again
  6. In the astrocyte the glutamate is metabolised as glutamine (a safe molecule)
  7. A glutamine transporter protein carries glutamine back to the presynaptic terminal
  8. When glutamine is in the terminal it can be metabolised by glutaminase into glutamate and repackaged as vesicles ready for release
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15
Q

What are the two families of Glutamate receptor?

A
  • Ionotropic
  • Metabotropic
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16
Q

What are Ionotropic glutamate receptors lablled as and what are three types?

A

iGluR

  • AMPA
  • Kainate
  • NMDA
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17
Q

At what speed do iGluR receptors function?

A
  • Fast
  • For excitatory synaptic transmission
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18
Q

What are metabotropic glutamate recpeptors labelled as and what are three types?

A

mGluR

  • Group 1: 1,5
  • Group 2: 2,3
  • Group 3: 4, 6, 7, 8
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19
Q

What family are metabotropic glutamate receptors apart of?

A

C GPCR’s

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20
Q

What speed do mGluR receptors function at?

A

Slower than iGluR

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21
Q

Where are mGluR binding sites?

A
  • In the N terminus
  • Venus fly-trap domain
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22
Q

In what form do mGluR receptors act?

A
  • As a dimer
  • Linked by their C terminal tails
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23
Q

Are Ionotropic glutamate receptors pentamers (like nAChR) or tetramers?

A

TETRAMERS

With 4 agonist binding sites

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24
Q

How many transmembrane domains does the iGluR receptor have and where is the dipping domain located?

A
  • 3 transmembrane domains
  • Dipping domain is between the 1st and 2nd strange region which goes into the membrane and crosses over
  • This dipping domain forms the lining of the channel
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25
Q

What is another term for the dipping domain?

A

The reentrant region

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26
Q

How many binding sites on the ionotropic glutamate receptor need to be occupied for full activation?

A
  • All 4 agonist binding sites
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27
Q

What is the structure of the NMDA ionotropic glutamate receptor?

A
  • GluN1
  • GluN2A-D
  • GluN3A-B

-Prototypical consists of 2 GluN1 and 2 copies of GluN2
- It is possible for one GluN2 to be substitued with a GluN3

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28
Q

Which units of NMDA bind glutamate?

A

GluN2 and 3

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29
Q

What does NMDA’s GluN1 bind to?

A

Glycine
for co-agonism

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30
Q

What is the structure of the AMPA ionotropic glutamate receptor?

A
  • GluA1-4
  • 4 Subunits which can from hetero-tetramers (2 copies of ne and 2 copies of another)
  • Or
  • Homo-tetramers (4 copies of the same subunit type)
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31
Q

What is the structure of the Kainate ionotropic glutamate receptor?

A
  • GluK1-3
  • Can form homo and hetero-tetramers

-GluK4-5

  • Can only assmble as hetero-tetramers with one of the GluK3 subunits
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32
Q

What do AMPA ionotropic glutamate receptors mediate?

A

Fast synaptic transmission (fast EPSP)

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33
Q

What are AMPA ionotropic glutamate receptors permeable?

A

Relatively permeable to Na, K and Ca but it depends on the sub-unit structure

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34
Q

How many sites need to be fill on an AMPA ionotropic glutamate receptor to be activated?

A

2

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35
Q

Where are Kainate ionotropic glutamate receptors found?

A

Pre-synaptic terminals

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36
Q

What are Kainate ionotropic glutamate receptors permeable to?

A

Much less peremable to Ca than some AMPA receptors

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37
Q

When an AMPA receptor contains Arginine what does this cause?

A

99% of GluA2 subunits are edited to yield arginine. This means that most AMPA cells are impermeable to calcium

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38
Q

What are NMDA ionotropic glutamate receptors permeable to?

A

Highly permeable to Ca

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39
Q

When does Mg block NMDA ionotropic glutamate receptors RMP?

A

At physiological concentrations of magnesium

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40
Q

What coagonist’s do NMDA ionotropic glutamate receptors need to operate?

A
  • Glycine
  • OR
  • D-serine
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41
Q

How many binding sites need to be occupied in a NMDA ionotropic glutamate receptor for it to be activated?

A

All 4
Because it needs a Glycine bound on GluN1

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42
Q

What are polyamine antagonists on NMDA ionotropic glutamate receptors?

A

Transmembrane regions that are targeted by endogenous signalling molecules

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43
Q

What is an example of a channel blocker for NMDA ionotropic glutamate receptors?

A

General anaesthetics and Ketamine

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44
Q

How is magnesium removed from blocking the NMDA ionotropic glutamate receptor?

A
  • Cell becomes slightly depolarised
  • Mg gets ejected from the channel
  • Allows ion influx through the channel
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45
Q

How many different metabotropic glutamate receptors are there?

A

8

  • Divided into 3 groups
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46
Q

What are the three groups of metabotropic glutamate receptors?

A
  • Group 1: 1, 5
    Somatodendritic location, Enhance NMDA, Inhibit K
  • Group 2: 2, 3
    Mostly nerve terminal location, inhibitory autoreceptors and heteroreceptors
  • Group 3: 4, 6, 7, 8
    Nerve termianl location, inhibitory autoreceptors and heteroreceptors
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47
Q

What are the 6 steps of ‘normal’ synaptic glutamate transmission?

A
  1. Current flow induced by AMPA activation leads to depolarisation
  2. Transmits to soma?
  3. Local depolarisation ‘deinactivates’ NMDA- greatly increased depolarisation, influx of Ca
  4. Transmits to soma!
  5. mGluR1 activation- Long/slow depolarisation which can lift Mg block= more depolarisation
  6. Synapse may become strengthened with repeated use (LTP)
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48
Q

How is GABA stored and released?

A
  • Stored in vesicles
  • Released in Ca dependent manner
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49
Q

How is GABA uptaken?

A
  • Transporter proteins into neurons and glia
  • Addition to vesicular pool
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50
Q

What is GAD?

A
  • Glutamic Acid Decarboxylase
  • Breaks glutamate into GABA
  • Is a good histochemical marker
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51
Q

What are the three GABA receptor families?

A
  • GABA A (ionotropic)
  • GABA B (metabotropic)
  • GABA C (subset of GABA A)
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52
Q

What occurs at a GABAergic terminal?

A
  1. GABA released via vesicles
  2. GABA signals on the post-synaptic synapse
  3. 2 ways it is turned off
  4. one way is GAT 1 goes back into the presynaptic terminal to be repackaged
  5. GAT 2 and 3 takes GABA into the astrocyte where it is metabolised by GABA transamonase and tricarboxylic acid cycle into glutamate
  6. Glutamate is synthesised into glutamine (safe molecule) by glutamine synthase
  7. Glutamine is released and taken into the presynaptic terminal
  8. It is converted into glutamate then into GABA by de-carboxylase (GAD)
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53
Q

How many CNS neurons are GABAergic?

A

Around 20% but is a transmitter in around 30% of all CNS connections

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54
Q

What are some long GABAergic projections?

A
  • Striatum
  • Substantia Nigra
  • Globus Pallidus
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55
Q

What type of channel is the GABA A ionotropic receptor?

A

Ligand gated chloride channel

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56
Q

What occurs when GABA binds to a GABA A receptor?

A
  • GABA binds
  • Increase in chloride permeability
  • The membrane potential is stabalises towards resting potential
  • The cell becomes inhibited
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57
Q

Do GABAergic receptors have lots of allosteric sites?

A

YES- GABA A

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58
Q

What are 3 compounds that enhance GABA A receptor function?

A
  • Sedatives
  • Anxiolytics
  • Anticonvulsants
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59
Q

What are two compounds that decrease GABA A receptor function?

A
  • Convulsants
  • Anxiogenics
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60
Q

How many GABA A receptor subunits does it have possible genes for?

A

19!

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61
Q

Where are GABA binding sites formed at?

A

Interfaces of beta and alpha subunits

and

At alpha and the neighbouring gamma subunit

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62
Q

What is the most common formation of subunits for GABA A?

A

One alpha

2 beta

one gamma OR delta

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63
Q

What does high affinity for Benzodiazepine at GABA A receptors require?

A

Requires a gamma subunit

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64
Q

What responds to leaking GABA

A
  • Becomes part of the neurochemical soup
  • Are some extrasynaptic GABA A receptors
  • Have high affinity for GABA
  • Produce tonic inhibition
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65
Q

What is the primary difference between extrasynaptic and synaptic GABA A receptors?

A

GABA A has a delta instead of a gamma subunit

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66
Q

What are extrasynaptic GABA A receptors targets for?

A
  • Alcohol
  • Neurosteriods
  • Some effects of anaesthetics
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67
Q

Where are GABA B metabotropic receptors found?

A

pre and post synaptically

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68
Q

How many sybunits do GABA B metabotropic receptors have?

A

2

GABA B1

GABA B2

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69
Q

How do metabotropic GABA B receptors operate?

A

As a dimer

GABA B1- binds GABA

GABA B2- interacts with the g-protein Gi

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70
Q

What are three primary uses of GABA B metabotropic receptors?

A
  • To inhibit voltage gated Ca channels (inhibit transmitter release)
  • Open potassium channels (reducing post-synaptic excitability)
  • inhibit adenylyl cyclase via Gi
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71
Q

Where is there a high concentration of Glycine?

A

In the spinal cord but some in the brain

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72
Q

What are the Glycine transporter proteins?

A
  • GlyT1 (astrocytes throughout CNS)
  • GlyT2 (spinal cord)
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73
Q

Where do humans sourse glycine from?

A
  • Diet
  • Serine
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74
Q

How many subunits do glycine receptors have?

A

5- is a pentamer

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75
Q

What subunits do glycine receptors contain?

A
  • 3 alpha
  • 2 beta
  • Glycine binds with alpha and their neighbouring beta subunit
  • Alpha can form a homomeric third binding site
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76
Q

What are Renshaw cells?

A
  • Spinal cord interneurons
  • They release glycine onto motor neurons
  • Negative feedback regulation of motor neurons, antagonistic motor neurons
  • Stimulated by collaterals from alpha motor neurons
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77
Q

What two molecules will act on glycine receptors?

A
  • Taurine
  • Beta alanine
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78
Q

What diseases does Lytico-Bodig resemble?

A
  • Alzheimer’s
  • Parkinson’s
  • Motor neuron disease
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79
Q

What seeds eaten by the Chamorro tribe cause Lytico-bodig disease?

A

Cyad seeds containing BMAA

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80
Q

Where does BMAA act in the nervous system?

A

Is an agonist of all three types of ionotropic glutamate receptors

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81
Q

What is an example of bioaccumulation seen in bats?

A
  • When the chamorro people eat bats
  • The bats have eated the cyad seeds
  • BMAA is concentrated in their tissues
  • When eat the bat, causes excitotoxicity and lytico-bodig
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82
Q

What causes Lathyrism?

A

The consumption of legumes of the genus lathyrus

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83
Q

What neurotoxin is involved in lathyrism and how does it act?

A

OADP (glutamate analogue)

Acts on ionotropic glutamate receptors

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84
Q

What is another name for the disease Lytico-bodig?

A

Guam’s disease

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85
Q

Do exitatory amino acids have long or short pathways?

A

Long

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86
Q

Do inhibitory amino acids tend to have long pathways?

A

Short- local interneurons

87
Q

Are amino acid transmitters good drug targets?

A

No

They are too ubiquitous. Hard to be precise and specific

Monoamines are better targets because we can target ina more precise manor

88
Q

What are the 4 monoamines?

A
  • Noradrenaline
  • Dopamine
  • 5HT (serotonin)
  • Histamine
89
Q

Is ACh a monoamine?

A

No, even though it has one amine group, it has its own class of transmitter

90
Q

What is a step-by-step of a typical monoamine synapse?

A
  1. Neurotransmitter is packaged by VMAT transporter protein
  2. Synthesis occurs in the presynaptic nerve terminal
  3. Have calcium dependent vesicular release
  4. When released, can act on post and pre-synapses
  5. Termination is through reuptake
  6. Uses MAO and COMT for metabolism
91
Q

Where is Monoamine oxidase A (MAO) located?

A

The outer membrane of the mitochondria

92
Q

Where is COMT located?

A

Is associtated with the membrane so can metabolise intracelllular neurotransmitters

93
Q

Do monoamines diffuse more or less than the amino acid neurotransmitter?

A

The are longer and have more diffusion projection

94
Q

How specific are the monoamines?

A
  • Not very specific
  • They have a modulatory role over multiple brain pathways and circuits
  • Some specifics however, such as dopamine in motor systems
95
Q

Which is the only monoamine that is not a catecholamine and what does this mean?

A
  • Serotonin
  • Means that it is not derived from tyrosine
96
Q

How was serotonin discovered as a neurotransmitter?

A

Following the discorvery of LSD

97
Q

What is serotonin derived from?

A

Dietary tryptophan

98
Q

What is serotonin involved in?

A

Sleep

appetite

thermoregulation

pain

mood

99
Q

What is serotonin’s long name

A

5-Hydroxytryptamine

100
Q

What are the steps of synthesis of 5HT?

A
  1. Hydroxylate tryptophan via tryptophan hydroxylase 2
  2. Remove the carboxylic acid group via DOPA decarboxylase
101
Q

What is involved in 5HT metabolism?

A

MOA

Aldehyde dehydrogenase

102
Q

Where are serotonergic pathways found?

A
  • Raphe nuclei in the brainstem
103
Q

How many variants of 5HT receptors are there?

A
  • 14
  • 5HT1-7 with variants
104
Q

Which 5HT receptor is the only ligand-gated cation channel?

A

5HT3

105
Q

Which 5HT receptors couple with Gi and what does this mean for signalling?

A
  • 5HT1
  • 5HT5
  • Decreases cAMP
106
Q

Which 5HT receptors couple to Gs and what does this mean for signalling?

A
  • 5HT4
  • 5HT6
  • 5HT7
  • Increases cAMP
107
Q

Which 5HT receptors couple with Gq and what does this mean for signalling?

A
  • 5HT2
  • Increase in inositol phosphates (IP3) and calcium
108
Q

Does serotonin act in the PNS or the CNS?

A

BOTH

109
Q

What would a problem be for the use of drugs targetting serotonin uptake and metabolism mechanisms?

A
  • Pathways are common to all serotonergic synapses
  • Would also effect noradrenaline and dopamine
  • Would be better to target the receptors themselves
110
Q

Where is the most preffered drug action in a receptor?

A

Allosteric modulation is preferred to antagonist and agonists

111
Q

How is adrenaline and noradrenaline synthesised?

A
  1. Tyrosine is hydrolysed by tyrosine hydroxylase
  2. DOPE decarboxylase breaks down DOPA
  3. this causes dopamine
  4. if dopamine beta-hydroxylase is present, noradrenaline is formed
  5. If phenylethanoalamine and N-methyltransferase are present then adrenaline is formed
112
Q

How does COMT act?

A

Adds a methyl group onto one of the hydroxyl’s on the catechol group

113
Q

How does MAO act?

A

It adds/replaces the amine group with an aldehyde group

114
Q

How many noradrenergic neurons are there in the brain?

A

20,000

10,000 on each side

115
Q

Where is noradrenaline located in the brain?

A
  • Locus Coeruleus
    Which projetcs across a wide range of brain areas and makes millions of synapses
  • Lateral tegmental area
    Projects into the spinal cord and the solitary nucleus
116
Q

What does the solitary nucleus control for?

A

Peripheral reflexes

117
Q

How does noradrenaline influence the autonomic nervous system?

A

crossing over between peripheral and central pathways

118
Q

How does noradrenaline synapse?

A
  1. Have nerve terminals and synapses but the axons have swellings called varicosities
  2. They are equivalent to nerve terminals and contain the same machinery such as vesicles and mitochrondia
  3. As the axon makes its way through the cell body to the nerve terminal’s target, it makes connections with multipple neurons that it crosses over on the way
  4. We end up with a large range of synapses
  5. It is more likely to get neurotransmitter leaking out over an area (local hormone effect)
  6. Many drugs target here
119
Q

What is EMT?

A

Extra-neuronal monamine transporter- not currently targeted by drugs as is peripheral

120
Q

How many adrenoceptor subtypes are there?

A
  • Alpha and beta
  • 10 subtypes
  • Present in CNS and PNS
121
Q

What are three therapeutic drugs at noradrenergic locations?

A
  • Dexmedetomidine: Exploits the arousal role and is used to keep people in comas in intensive care by acting on alpha 2 receptor
  • Mirtazapine: Acts on adrenoreceptors (alpha 2) in the CNS- antidepressant
  • Clonidine: Used as a anti-hypertensive agent (only acts centrally)
122
Q

What is an example of a non-therapeutic noradrenergic drug?

A

Cocaine

123
Q

What brain disorders is dopmaine involved in?

A

Parkinsons

Schizophrenia

ADHD

Substance abuse

Endocrine disorders

124
Q

Does Dopamine have long or short pathways?

A
  • Shorter than noradrenaline
  • Has some diffuse characteristics
  • Also some discrete pathways- such as motor
125
Q

What neurotransmitter can dopamine be converted into?

A

Noradrenaline

126
Q

What methodology does dopamine use to synapse?

A

Diffuse modulatory transmission using varicosities

127
Q

How many synapses does a neuron of the substantia nigra make?

A

500, 000 synapses in the striatum
(striking example of varicosities function)

128
Q

What percentage of the brain is that of dopiminergic neurons?

A

<0.0002%

129
Q

What enzymes cause dopamine degredation?

A
  • MAO
  • COMT
  • Aldehyde dehydrogenases
130
Q

What is the product of dopamine degredation?

A

Homovanillic acid (HVA)

131
Q

What are the 4 dopaminergic pathways?

A
  1. Mesocortical pathway (ventral tegmentum into the cortex)
  2. Nigrostriatal pathway (substantia nigra to the striatum)
  3. Lubero-infudibular pathway (hypothalamus into the medio- eminans and pituitary)
  4. Mesolimbic pathway (ventral tegmentum into the limbic system)
132
Q

What brain area does the dopaminergic pathways cross-talk with?

A
  • Feedback to the locus coerelus
  • Input from the dopaminergic pathway into the noradrenergic
133
Q

What are the two receptor categories of dopamine receptors?

A
  • D1 like
  • D2 like
134
Q

What G-protein does D1 like dopaminergic receptors signal through?

A
  • D1
  • D5

Transmit via Gs which causes an increase in cAMP

135
Q

What G-protein does D2 like dopaminergic receptors signal through?

A
  • D2
  • D3
  • D4

Transmits through Gi so there is a decrease in the levels of cAMP

136
Q

What is the pathway/steps through which dopamine regulation occurs?

A
  1. When cAMP changes due to D1 like and D2 like receptors, it activates PKA
  2. PKA phosphorylates DARPP-32 (dopamine and cyclic AMPA regulated phospho-protein)
  3. DARPP-32 has negative effects on phosphase 1as it moves the phosphate group from proteins
  4. If we inhibit it, we will increase phosphoproteins in a cell
  5. This changes the cell behaviours
  6. Also, phosphorylated DARPP-32 can be converted back to its non-phosphorylated state by calcineurin
137
Q

What receptor does Yohimbine act on?

A

Alpha 2 adrenoreceptor antagonist

138
Q

How does Yohimine act in rodents?

A
  • A highly effective aphrodisiac
  • Encourages male mice to ‘have another go’ even when past the point of sexual exhaustion
  • Less effective in humans because of intellectual aspects of sex
139
Q

What are the two main cell groups of cholinergic cells?

A
  1. Pedunculopontine/ laterodorsal tegmentum (projects to the thalamus)
  2. Magnocellular forebrain (nucleus psasalis to the cortex and septal neurons to the hippocampus)
140
Q

Where are cholinergic neurons found in the periphery?

A

Autonomic ganglia, motor synapses and in the skeletal neuromuscular junction

141
Q

What structure do nicotinic ACh receptors from?

A
  • Pentameric with 16 suntypes in humans
  • They form built in ion channels
  • 2 + ACh sites
142
Q

Are nicotinic receptors excitatory or inhibitory?

A

Excitatory

143
Q

What are 2 nicotinic ACh agonists?

A
  • Nicotine
  • Suxamethonium
144
Q

What are 3 nicotinic ACh receptors?

A
  • Atracurium
  • Tubocurarine
  • Alpha BTX
145
Q

What structure do muscarinic ACh receptors form?

A
  • Monomeric with 5 receptor types (M1-M5)
  • They have a binding site for G protein
  • Have 1 ACh site
146
Q

Are muscarinic ACh receptors excitatory or inhibitory?

A

Inhibitory or excitatory (inhibits M current)

147
Q

What are 2 agonists of muscarinic ACh receptors?

A
  • Muscarine
  • Pilocarpine
148
Q

What are two antagonists of muscarinic ACh receptors?

A
  • Atropine
  • Hyoscine
149
Q

Which are faster, nicotinic or muscarinic ACh receptors?

A

Nicotinic are faster

150
Q

What are the roles of ACh in different areas of the brain?

A
  • Pontine nuclei- arousal, sleep/wake
  • Magnocellular forebrain- arousal
  • Septohippocampal- learning (short term)
  • Striatal interneurons- motor control
151
Q

What does ACh knockout reveal?

A
  • Reveals some functions if remove from a germline of an animal (its born without ACh)
  • Compensation is a problem with this so showed little difference
  • Inducible knockouts reveal more information
152
Q

What are the steps at a cholinergic synaptic terminal?

A
  1. Is synthesised from acetylcholine co-enzyme A and choline by acetyl transferase
  2. ACh is pachaged by transporter proteins
  3. Is released via calcium dependent vesicular pathway
  4. Signals across the synapse
  5. Is terminated by acetylcholine esterase to make a choline and an acetate
  6. Choline is recycled in the presynpatic nerve terminal
153
Q

How does a neuronal nicotinic ACh synapse differ for a neuromuscular one?

A
  • Receptors are found on presynaptic nerve terminals and on the outside of the synapse
  • Neuronal act in a neuromodulatory manor as ACh from other synapses can activate the neuronal nicotinic receptors
  • The neuronal presynaptic terminal are highly permeable to calcium which enters to stimulate vesicular release and depolarises the membrane to activate voltage gated calcium channels
  • Neuronal synapses modulate a wide range of other transmitters too.
154
Q

How do muscarinic ACh synapses differ from the nicotinic receptors?

A

Can get presynaptic muscarinic receptors (M2) which are inhibitory auto receptors that regulate release

155
Q

What do M2 and M4 muscarinic receptors signal through at synaptic transmission?

A
  • Adenylyl cyclase
  • Gi
  • cAMP
  • PKA
156
Q

What do M1, M3, M5 muscarinic receptors signal through at synaptic transmission?

A
  • Phospholipase C
  • PKC
  • Calcium signalling
157
Q

What family are nicotinic ACh receptors a part of?

A

Cys-loop receptor superfamily

158
Q

Where are Skeletal muscle nAChR binding sites?

A
  • 2 alpha 1, one epsilon, a delta and a beta 1
  • 2 binding sites at alpha subunits with the neighbouring delta and epsilon (gamma for foetus)
  • Its permeabl to sodium and potassium and calcium at some combinations
159
Q

What are the three different structures of neuronal nicotinic ACh receptors?

A
  1. 2 copies of alpha 4 and 2 copies of beta 2. Binding sites are at the interfaces of the alpha and the anti-clockwise neighbours (beta)
  2. Homomeric receptor with 5 alpha 7 copies, it has 5 binding sites (extra synaptic perhaps)
  3. 3 beta 4 subunits and 2 alpha 3. Is found in the brain, also found in the autonomic ganglia.
160
Q

What are the similarities of the ionotropic ACh receptors?

A
  • All have 4 transmembrane domains and a large N terminal extracellular domain. Have a loop between the third and fourth transmembrane domains
  • 5 M2 domains forms the channel lining
  • Have a regulatory site
161
Q

How does the channel lining opening and closing work?

A
  • In the 5 M2 domains, there is a leucine residue halway down and points into the centre of the channel
  • Leucine is large and hydrophobic
  • M2 domain swings the leucine out of the domain and swings the hydrophillic serine residue into the centre
  • Serine is small and hydrophililc which favours the entry of cations
162
Q

Where are the binding sites of muscarinic ACh receptors located?

A

The top of the 7 transmembrane domains

163
Q

What is the main issue with creating drugs for muscarinic ACh receptors and how can we overcome this?

A
  • Agonist binding site is highly conserved (only a couple of amino acids difference)
  • Very few selective agonists or competative agonsits
  • Allosteric site is better for modulating the effects of ACh
  • Can have bifunctional ligands which target both allosteric and ACh binding sites
164
Q

What is the best antagonist for muscarinic ACh receptors?

A

Darifenacin (30-fold M3 selective) for an overactive bladder

165
Q

What causes an M current?

A
  • The PIP2 gated potassium channels
  • When these channels are open, its harder to excite the receptor as the cell is more hyperpolarised
166
Q

How do we alter the M current to allow receptor excitation?

A
  • Activation of M1, 3, 5 (Gq) leads to depletion of PIP2
  • This shuts off the M current
  • Cell becomes more excitable
167
Q

Where is histamine found?

A
  • In mast cells
  • In magnocellular neurons in the posterior hypothalamus
168
Q

What type of animal are histamine pathways moost and least developed in?

A
  • Most developed in lower vertebrates
  • Least developed in higher animals
169
Q

How many histamine neurons are there in the brain and when are they active/inactive?

A
  • Around 64000 cells
  • Active during wake
  • Inactive during sleep
170
Q

What amino acid is histamine derived from?

A

Histadine

171
Q

How is histamine synthesised?

A
  • Histadine is decarboxylated by Histadine decarboxylate to produce histamine
172
Q

How is histamine metabolised?

A
  • MAO
  • Histamine N-methyltransferase
173
Q

How many different types of histamine receptors are there and where are they found?

A
  • 4 (H1-H4)
  • H1-3 are found in the brain
  • H4 is found in the periphery
174
Q

Which G-proteins are the different histamine receptors coupled with?

A
  • H2- coupled through Gs to adenylate cyclase pathway
  • H3, 4- coupled through Gi to the adenylate cyclase pathway
  • H1- coupld through Gq to the PLC pathway
175
Q

Which Histamine receptor can exist post-synaptically?

A
  • H3
  • Can act as a pre-synaptic auto receptor
176
Q

How is Histamine terminated at the synapse?

A
  • Is a mystery
  • But, there may be reutake via a transporter

-OR

  • HNMT in the synaptic cleft may modify histamine to become inactive
177
Q

What are H1 antagonists used for?

A
  • Used widely therapeutically (allergies)
  • Some cross BBB to produce marked sedation (if cross the blood-brain barrier, other drugs can target H1 and act to sedate)
178
Q

What are H2 receptors used for?

A
  • Theraprutic use for ulcer treatment
  • Not much BBB penetration
179
Q

What are H3 receptors used for?

A
  • Lots of new ideas but nothing yet
  • Perhaps cognition, sleep, schizophrenia and pain
180
Q

What are neuropeptides?

A

Diveerse range of small proteins that have vital signalling roles across the body

181
Q

Where are Neuropeptides synthesised?

A
  • In the soma as there are no ribosomes in the nerve terminal
  • Often produced as an inactive pro transmitter that needs to be cleaved at the nerve terminal to produce the finished transmitter
182
Q

How are neuropeptides stored?

A
  • Storedin vesicles, Calcium dependent release
183
Q

Where do neuropeptides act?

A
  • Post-synaptic action on GPCR’s
184
Q

How are Neuropeptides seen as neuromodulators over neurotransmitters?

A
  • They have no obvious fast roles
  • They often co-exist with other classical transmitters to extend the classical dynamic range
185
Q

Whats an example of how neuropeptides co-transmit?

A
  • In the periphery, peptides (VIP) co-exist with ACh in parasmpathetic innervation of salivary glands
  • When there is low firing, we only get ACh released
  • When there is high firing, we get both ACh and VIP released to extend the dynamic range of the response
186
Q

How many different peptide receptors are there and what family do they derive from?

A
  • 118
  • Family A and B
187
Q

What is an example of a Purine?

A

Adenosine

188
Q

How does Adenosine act in the synapse?

A
  • As a neurotransmitter/modulator
  • Not through vesicular release
  • Receptors can form heterodimers with other family A and C GPCRS (dopamine and mGluR)
  • May be more protective than transmissive as acts to stabalise over-activity
189
Q

How many receptors of adenosine are there and what are they?

A
  • 4

-A1, A2A, A2B, A3

190
Q

What is an example of an adenosine antagonist?

A

Caffeine at A2A (will block all 4 receptor types however)

191
Q

Where is melatonin made?

A

Pineal gland

192
Q

What amino acid is melatonin synthesised from?

A
  • Indirectly from tryptophan
  • Directly from 5HT
193
Q

How many receptors does melatonin have?

A
  • 2
  • MT1 and MT2 GPCR’s
194
Q

Where are melatonin receptors found?

A
  • Brain
  • Retina
195
Q

How is melatonin released?

A
  • Secretion rather than transmission
  • Driven by circadian light cycle from retinal input
196
Q

What is melatonin a possible drug target for?

A
  • Anti-jet lag drugs
  • Anti-depressants
197
Q

How is Nitric Oxide synthesised?

A
  • Is produced by Nitric oxide synthase (NOS)
  • Controlled by intracellular Calcium levels
198
Q

How does Nitric oxide produce inhibitory and exctiatory effects?

A
  • Through the control of cGMP levels
  • May be other mechanisms too
199
Q

What does volume action mean when speaking about nitric oxide?

A
  • Does not act synaptically
  • Diffuses over a wide area up to 400 micrometers away from release (acts over seconds to minutes)
200
Q

What are some important roles of Nitric oxide?

A
  • Acts as a cotransmitter
  • Roles in LTP and LDP
  • Roles in neurotoxicity
201
Q

What are lipids formed from?

A

Arachidonic acid

202
Q

What are 3 examples of lipids molecules?

A
  • Prostaglandins
  • Leukotrienes
  • Endocannabinoids
203
Q

What was the origional hypothesis surrounding cannabinoids?

A
  • As they are lipid soluble, thought they acted similarly to general anaethetics
204
Q

What are cannebinoids receptors?

A
  • CB1, CB2
205
Q

Where are cannebinoid receptors expressed?

A

Throughout the CNS and PNS therefore have a wide range of potential functions

206
Q

What is the issue with research around cannabinoids?

A
  • THC is a controlled substance and this is what causes receptors CB1 and 2
207
Q

What are endocannabinoids?

A
  • Lipid molecules
  • We produce our own endogenous signalling molecules that act on CB1 and CB2 receptors
208
Q

What are the two main endocannabinoids?

A
  • Anandamide
  • 2-arachidonoyl glycerol (2-AG)
209
Q

What are endocannabinoids synthesised from?

A
  • Membrane lipids
  • They are not stored but synthesised as needed.
210
Q

How are endocannabinoids terminated?

A
  • Through endocannabinoid membrane transporter (EMT)
211
Q

What are the steps involved with endocannabinoid action at the synapse?

A
  1. Activation of metabotropic receptors can lead to the production of endocannabinoids
  2. They move into the synapseand act at CB1 (post-synaptic) in an autocrine fashion
  3. May also have pre-synaptic nerve-terminal retrograde transmission (transmission occurs backward into the presynaptic terminal)
  4. These receptors are coupled with Gi adenylyl cyclase, preventing glutamate release (feeding back to lessen glutamate in the synapse)
  5. They can also leak out of the synapse into other synapses (GABAergic synapses for example)
  6. The other synapse may have CB1 receptors on the terminal- could then act and reduce cAMP and in turn damped down GABA release
212
Q

What are the three ways cannabinoids can act in synapses?

A
  • Post-synaptically
  • Pre-synaptically (retrograde)
  • Paracrine (Extra- synapses)
213
Q

What does lean consist of?

A
  • Over the counter medications
  • Codein and promethazine
214
Q

What sensations does lean produce?

A
  • Euphoria (codeine acting at opioid receptors)
  • Sedation (promethazine acting act H1 histamine receptors)

(codeine content can cause addiction)

Drugs and the Brain (9 decks)

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