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Disease in the brain > Cholinergic signalling (done) > Flashcards

Cholinergic signalling (done) Flashcards

1
Q

Which NS is ACh found in?

A

Both PNS & CNS

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2
Q

What are the main roles of ACh?

A
  • Major function in movement (muscle contraction in PNS, motor control in CNS)
  • Roles in attention, learning & memory
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3
Q

What does ACh do at the NMJ?

A

ACh mediates direct control of skeletal muscle tension at NMJ

(Modulation of timing & tension in the cardiac & smooth muscle mediated by ACh released by postganglionic parasympathetic neurons

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4
Q

What are the 2 classes of cholinergic receptors?

A
  • Nicotinic (nAChR)
  • Muscarinic (mAChR)
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5
Q

Who discovered ACh & how?

A

Otto Loewi (1921)

Used 2 frog hearts & stimulated the vagus nerve - HR slowed down, he realised vagus nerve must be releasing signals onto heart

Found vagus nerve was supplying chemical substances to organs = ACh

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6
Q

Who were the 2 guys involved in discovering ACh?

A

Henry Dale & Otto Loewi

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7
Q

How many clusters of cholinergic projections are there?

A

8 clusters

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8
Q

What are cholinergic projection neuron clusters (Ch)1-4 called?

A

Medial Septal Group

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9
Q

What is the Medial Septal Group?

A

Ch1-4 in the basal forebrain target cortical & limbic structures (attention, learning, memory)

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10
Q

What are cholinergic projection neuron clusters (Ch)5-6 called?

A

Pontine Cholinergic System

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11
Q

What is the Pontine Cholinergic System?

A

Ch5-6 in the caudal midbrain target the thalamus, midbrain & cerebellum (sleep, arousal & motor function)

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12
Q

What are Ch7-8 cholinergic projections?

A

In the midbrain target the brainstem & midbrain (motor/sensory function)

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13
Q

What are the 2 sets of neurons in the PNS?

A
  • Preganglionic neurons
  • Postganglionic/postsynaptic neurons
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14
Q

What are preganglionic neurons?

A
  • Cell bodies in the brain & spinal cord (CNS)
  • Synapses on neurons in an autonomic ganglion located near or in effector organs
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15
Q

What are postganglionic/postsynaptic neurons?

A
  • Cell bodies in the ganglion
  • Synapses on the effector
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16
Q

What is a ganglion?

A

Collection of PNS neuron cell bodies

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17
Q

What can the neurons in the PNS do depending on receptors?

A

Can stimulate or inhibit muscle contrations depending on receptors

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18
Q

What is ACh synthesis catalysed by?

A

By the enzyme choline acetyltransferase (ChAT)

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19
Q

What does ChAT (choline acetlytransferase) do to make ACh?

A

Transfers the acetyle group (CH3CO-) from acetyl-Coenzyme A (Acetyl-CoA) to choline

Forming ACh

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20
Q

What is ACh synthesised from?

A

From dietary precursors

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21
Q

What are the dietary precursors that make choline?

A
  • Egg yolks
  • Liver
  • Fish
  • Grains
  • Nuts
  • Soya
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22
Q

What are the dietary precursors that make acetyl-CoA?

A

From breakdown fo glucose

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23
Q

What are the 6 stages of synaptic ACh synthesis, release & recycling? (Short version)

A

1 - Synthesis
2 - Storage
3 - Release
4 - Effect
5 - Recycling
6 - Reuptake

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24
Q

What are the 6 stages of synaptic ACh synthesis, release & recycling? (Long version)

A

1 - Synthesis = Cytosolic choline acetlytransferase (ChAT) synthesis ACh

2 - Storage = Vesicular ChT loads ~10,000 ACh molecules into each 40-50nm vesicle

3 - Release = Action potential causes Ca2+ –> mediated vesicular release (~300 vesicles/AP)

4 - Effect = ACh diffuses across the synapse & activates post-synatic recpetors (EPSP, ~2ms)

5 - Recycling = ACh is metabolised to choline + acetate by acetylcholine esterase (AChE)

6 - Reuptake = ~80% of choline is taken up by presynaptic cell for resynthesis (Na+ dependent channel)

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25
Q

What is a motor unit at the NMJ?

A

Single motor neurone & all muscle fibres innervated

(Each motor unit functions as an individual unit)

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26
Q

What is focal innervation?

A

1 synapse per muscle fibre = innervation from 1 motor unit only

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27
Q

What is the safety factor at the NMJ?

A

8-10x the amount of ACh required is released

This means = 100% sucess rate of muscle contraction when a motorneurone fires

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28
Q

Where does muscle innervation come from in the SC?

A

The anterior ventral horn

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29
Q

What is the process of a signal reaching the NMJ?

A

–> Cell bodies in anterior ventral horn of SC

–> Signal goes to motor neurons (Alpha motor neurons)

–> Goes to innervate musce fibres at the NMJ –> by activating Nicotinic receptors on muscle fibre

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30
Q

Refer to slide 3.4 for diagram of NMJ

A

:)

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31
Q

What are the 3 stags of ACh recycling & resynthesis?

A

1 - Degredation

2 - Reuptake

3 - Resynthesis

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32
Q

What happens in the Degredation (1) stage of ACh recycling & resynthesis?

A
  • ACh can’t be transported back into the neuron
  • It is broken down in the synaptic cleft by the enzyme AChE in microseconds into:

ACh = choline + acetate

33
Q

What happens in the Reuptake (2) stage of ACh recycling & resynthesis?

A
  • Choline taken back up into presynaptic cholinergic nerve terminal by energy dependent co-transport system w Na+
  • Choline reuptake is the RATE LIMITING STEP in ACh synthesis
34
Q

What happens in the Resynthesis (3) stage of ACh recycling & resynthesis?

A

Choline acetyltransferase (AhT) in neuronal cytosol combines choline w acetyl coenzyme A (to mkae ACh)

Acetyle CoA = derived from mitochondria & Krebs cycle

35
Q

Bit of interesting context & might help u remember - he said this won’t be on the exam:

Nerve gas & the NMJ:

A

VX & sarin nerve gas are organophosphates (like pesticides):

  • Potent AChE inhibitors
  • Prevent degredation of ACh –> builds up in motor end plate preventing muscle relaxation
  • Rapidly leads to death via muscle paralysis & asphyxiation
36
Q

What are the 2 types of ACh recpetors?

A

Nicotinic & Muscarinic receptors

37
Q

What type of channel are Nicotinic recptors & how do they work?

A

Ionotropic/ion channels

They directly activate neurons by changing ion concentrations

38
Q

Which type of ACh receptor is an ionotropic channel?

A

Nicotinic receptors

39
Q

What type of channel are muscarinic recpetors & how do they work?

A

Metabotropic/G protein-coupled receptors

They use intracellular 2nd messengers

40
Q

Which type of ACh receptor is a metabotropic/G protein couped receptor?

A

Muscarinic receptors

41
Q

What are the characteristic of Nicotinic receptors?

(4 points)

A
  • Pentameric channel (5 subunits)
  • 11 subtypes
  • Major recpetors at NMJ
  • Also found in neurons
42
Q

What are the characteristics of Muscarinic receptors?

(2 points)

A
  • 5 subtypes (M1-M5)
  • Can be excitatory (M1, 3, 5) or inhibatory (M2, 4)
43
Q

Are nicotinic receptors excitatory or inhibatory?

A

They are ALL excitatory

44
Q

What do nicotinic receptors mediate?

A

They mediate fast neurotransmission in PNS

& excitation/neuromoduclaiton in CNS

45
Q

What is the structure of Nicotinic recptors like?

A
  • They are Pentameters –> which contain at least 2 alpha subunits
  • Each a subunit binds one molecule of ACh
46
Q

Why are the 2 alpha subunits in Nicotinic receptors so important?

A

Subunit composition affects:

  • Ion selctivity
  • Agonist affinity
  • Localisation
  • Kinetics
  • Desnsitisation
47
Q

What are the 2 subdivisions of Nicotinic receptors?

A
  • Muscle-type receptors at te NMJ (N1 or Nm)
  • Neuronal subtypes (N2 or Nn)
48
Q

What are the 2 divisions of muscle-type Nicotinic receptors at the NMJ? (N1 or Nm)

A
  • Embryonic form (α1, β1, γ, and δ subunits)
  • Adult form (α1, β1, δ, and ε subunits – higher conductance, shorter opening time)
49
Q

What are the neuronal subtypes of Nicotinic recrptors like?

A

They are a combination of twelve different nicotinic receptor subunits: α2−α10 and β2−β4.

–> Homomeric (one type of subunit)
–> Heteromeric (at least one α and one β subunits)

50
Q

Where are the 5 subtypes of Muscarinic AChRs found?

A
  • All found in CNS
  • M1-M4 also found in other tissues
51
Q

What family of receptors are muscarinic receptors in?

A

Part of a large family of G-protein coupled receptors

(They use an intracellular secondary messenger system –> to transmit signals inside cells)

52
Q

Which of the subtypes of muscarinic AChRs are excitatory vs inhibitory & what are they coupled with?

A

Excitatory –> M1, M3 & M5 (Gq coupled)

Inhibitory –> M2 & M4 (Gi coupled)

53
Q

Where are each of the excitatory muscarinic AChRs found?

A

M1 = enteric & neuronal

M3 = glandular & vascular

M5 = CNS

54
Q

Where are each of the inhibitory muscarinic AChRs found?

A

M2 = cardiac

M4 = CNS

55
Q

What are the actions of the excitatory muscarinic AChRs (M1, M3, M5)?

A
  • CNS excitation
  • Gastric acid secretion
  • Gastrointestinal motility
  • Glandular secretion
  • Contraction of visceral smooth muscle
  • Vasodilation
56
Q

What are the actions of inhibitory muscarinic AChRs (M2, M4)?

A
  • Cardiac inhibition
  • Presynaptic inhibition
  • Neuronal inhibition
57
Q

What is the cascade(?) action that happens when an agonist acts on an excitatory muscarinic AChR?

(Need to go back thru video to clarify this - just assuming from the slide lol)

A
  • ↑ IP3, DAG
  • ↑ Intracellular Ca2+ (Stimulation)
  • ↓ K+ conductance (Depolarisation)
58
Q

What is the cascade(?) action that happens when an agonist acts on an inhibitory muscarinic AChR?

(Need to go back thru video to clarify this - just assuming from the slide lol)

A
  • ↓ cAMP
  • ↓ Ca2+ channel (inhibition)
  • -K+ conductance (slow IPSP)
59
Q

Pls look at slide 4.4 for good diagram of division of cholinergic receptors

60
Q

Where are nicotinic & muscarinic both highly expressed?

A

In the cortex & hippocampus

Play a neuromodulatory role increasing (nicotinic) or decreasing (muscarinic) synaptic release probability

61
Q

Which muscarinic receptors are found in the following brain areas?

A

SN/VTA = mostly M5

Hippocampus = M1-M4

Cortex = mostly M1, M2, M4 (M2>M4)

Striatum = mostly M1, M4, M2 (M4>M2)

Cerebellum = mostly M2, M1 (M3>M4>M5)

62
Q

What can manipulation of ACh levels do to the brain?

A

It affects a range of cognitive functions –> particularly attention, learning & memory

ACh depletion also contributes to normal age-related cognitive decline

63
Q

What are the 3 types of drugs that are used to manipulate cholinergic transmission?

A
  • AChR agonists
  • Acetylcholinesterase (AChE) inhibitors
  • AChR antagonists
64
Q

What do AChR agonists do (the drug)?

A
  • Mimic the effects of ACh on AChRs
  • Nicotine & muscarinic receptors
  • Improve cognitive function
65
Q

What do Acetylcholinesterase (AChE) inhibitors do (the drug)?

A
  • Prevent ACh degredation & inc ACh levels at synapses
  • Improve cognitive function in AZs disease (e.g. Donzepil) –> irreversible inhibitors are toxic!!!
66
Q

What do AChR antagonists do?

A
  • Block the effects of ACh at receptors
  • Produce memory impairments as in AZs disease (e.g. scopolamine & atropine)
67
Q

What do AChR antagonist drugs do?

A
  • Block the effects of ACh at receptors
  • Produce memory impairments in AZs disease (e.g. scopolamine & atropine)
68
Q

What was the test used to prove that vigilance is controlled by ACh?

A

Vigilance tasks req sustained attention

Task: detecting rare & unpredictable target stimuli
- Letter or digits presented in random order
- Subject must respond to specified targets

Measures:
- Response time to target
- Omission & false alarms

69
Q

What did the study on ACh & vigilance show about scopolamine?

A

IMPAIRS vigilance task performance == slower responses, more errors

69
Q

What did the study on ACh & vigilance show about nicotine?

A

IMPROVES vigilance task performance == faster responses, less errors

70
Q

What does scopolamine induce?

A

“Transient memory impairments” -> it is used as a model of cognitive deterioration

(Scopolamine mimics age-related memory deficits)

71
Q

How has scopolamine helped developing drug treatments?

A

Cholinergic drugs to treat AZs disease (e.g. AChE inhibitors) are evaluated on their ability to reverse scopolamine-induced memory impairments

72
Q

How is cholinergic signalling involved in SZ?

A
  • Smoking unusually prevalent in Schizophrenics
  • Mutations in the nicotinic a7 receptor inc the chance of developing SZ
73
Q

How is cholinergic signalling involved in Parkinson’s?

A

Dopaminergic activity is heavily regulated by both muscarinic & nicotinic receptor activity

74
Q

How is cholinergic signalling involved in epilepsy?

A

Mutations in nicotinic receptors associated w Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

75
Q

How is cholinergic signalling involved in addiction?

A
  • Nicotine activates mesolimbic DA pathways, resulting in addiction
  • Deleting M5Rs (DAerigic neurones) reduces reinforcement & withdrawal related behaviours
76
Q

How is cholinergic signalling involved in Alzheimer’s disease?

A
  • Many neurologic & psychiatric impairments seen in AD are linked to disruption of the Cholinergic system
  • AChE-inhibitors are one of the ONLY available treatment options
76
Q

Summary slide for a bit of reading:

A
  • Cholinergic neurones deliver ACH throughout the PNS&CNS - effector molecule at NMJs, mediates autonomic NS actions in the periphery, roles in attention, cognition & motor control in the brain
  • ACh acts at inotropic nicotinic & metabotropic muscarinic receptors
  • Nicotinic receptors show functional diversity according to the subunit composition
  • Muscarinic receptors can be excitatory M1-type (M1/3/5) coupled to Gq/11 or inhibitory M2 type (M2/4) coupled to Gi/0
  • ACh receptors are abundant throughout the brain, however there are significant differences in expression profiles between subtypes
  • Abnormalities in the cholinergic system have been linked to many disease states incl AZs

Disease in the brain (22 decks)

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