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PHAR0002 > Lecture 4 - The Synapse > Flashcards

Lecture 4 - The Synapse Flashcards

1
Q

What is the difference between nicotinic and muscarinic ACh receptors?

A

Nicotinic ACh receptors - FAST
- ionotrophic (ligand-gated ion channels)
- directly allow the passage of ions across the cell membrane
- activated by nicotine & ACh

Muscarinic ACh receptors - SLOW
- metabotrophic
- are not ion channels - activate intracellular signalling pathways through the use of G-proteins
- activated by muscarine & ACh

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2
Q

Where are nicotinic ACh receptors found?

A

In the postsynaptic membrane of the neuromuscular junction

In the autonomic ganglia

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3
Q

What are the effects of activation of nicotinic ACh receptors?

A

Depolarisation of the postsynaptic membrane and the initiation of muscle contraction / transmission of signals to other neurones

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4
Q

Where are muscarinic receptors found?

A

Locations including the heart, smooth muscle and glands

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5
Q

What are the effects of activation of muscarinic receptors?

A

Include:
Decreased heart rate, increased glandular secretion, smooth muscle contraction

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6
Q

What does it mean that the EPP is a graded potential?

A

It’s amplitude can vary depending on the amount of ACh released by the presynaptic terminal - i.e. the number of ACh receptors activated

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7
Q

What is the ‘End plate potential’ (EPP)?

A

Depolarisation of the muscle fibre membrane at the neuromuscular junction (NMJ) in response to the release of ACh from the presynaptic terminal of the motor neurone

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8
Q

How is the EPP generated?

A
  1. Action potential arrives at the presynaptic terminal of a motor neurone - causing depolarisation of the membrane
  2. Depolarisation causes voltage-gated Ca2+ channels to open
  3. Influx of Ca2+ causes release of ACh from presynaptic terminal into synaptic cleft
  4. ACh diffuses across synaptic cleft and binds to nicotinic acetylcholine receptors (nAChRs) on the postsynaptic membrane of the muscle fibre
  5. Binding of ACh causes Na+ channels to open
  6. Na+ influx causes depolarisation of postsynaptic membrane - generating end-plate potential
  7. If the EPP is above threshold - triggers AP in muscle fibre
  8. Action potential propagates along muscle fibre - causing muscle contraction
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9
Q

What causes the synaptic delay?

A

The time taken to release ACh into synaptic cleft, and the time it takes to diffuse across and bind to receptors

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10
Q

What is the difference between the EPP and AP?

A

EPP is a graded potential - its amplitude can vary depending on the amount of ACh released by the presynaptic terminal and it can trigger an AP in the muscle fibre if it reaches above threshold

AP is an all-or-nothing potential - membrane potential must reach threshold

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11
Q

Summarise the relationship between EPP and AP

A

EPP must reach threshold to generate AP

I.e. enough ACh must be released so that EPP is of a high enough amplitude to reach threshold

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12
Q

Describe the (re-)synthesis of ACh (transmitter)

A
  1. ACh hydrolysed into acetate + choline by acetylcholinesterase
  2. Choline uptaken by choline uptake carrier
  3. Acetate synthesised in the Krebs cycle and then forms acetyl coenzymeA (AcCoA) in the mitochondria
  4. AcCoA + choline = ACh (catalysed by acetylcholinesterase)
  5. Vesicular ACh transporters (VAChT) package ACh into secretory vesicles (using the movement of H+ ions out to drive ACh into cells)
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13
Q

The presence of what molecule identifies an ACh / cholinergic nerve fibre?

A

Choline acetyltransferase

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14
Q

What is myasthenia gravis characterised by?

A

Muscle weakness & fatigue (particularly in voluntary muscles that control eye movements, facial expressions, chewing, swallowing, speaking & limb movements)

Difficulty breathing / swallowing

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15
Q

What causes myasthenia gravis?

A

Autoimmune disorder

Immune system produces antibodies that bind to nicotinic acetylcholine receptors (nAChRs) on the postsynaptic membrane of neuromuscular junctions, therefore ACh cannot bind

This decreases both the number and sensitivity of available receptors to ACh

Decreased binding of ACh decreases EPP - so it can no longer reach threshold = transmission failure

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16
Q

What is the EPP and what does its amplitude depend on?

A

Local graded potential
Occurs where ACh receptors are located on the post-synaptic membrane

Inc ACh = more receptors activated = increased EPP (larger amplitude)

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17
Q

How is neurotransmission terminated? Can this process be modulated?

A

Acetylcholinesterase hydrolyses ACh —> acetate + choline

Yes this process can be modulated

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18
Q

How can myasthenia gravis be treated simply?

A

Using AChE (acetylcholinesterase) inhibitors

Stops breakdown of ACh - so that it can re-bind - increasing [ACh] - increasing EPP above threshold = transmission success

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19
Q

How many molecules of ACh are contained in a single vesicle?

A

Estimated ~10,000 molecules

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20
Q

How many receptors are there at a typical neuromuscular synapse?

A

~ 10-100

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21
Q

What are the names of 3 AChE inhibitors (that can be used to modify activity of AChE in the treatment of myasthenia gravis)

A

Edrophonium (short-acting)
Neostigmine (longer-acting)
Pyridostigmine (longer-acting)

22
Q

What are the 3 targets of drugs affecting neurotransmission?

A
  1. Presynaptic - affecting neurotransmitter SYNTHESIS
  2. Presynaptic - inhibiting neurotransmitter RELEASE
  3. Postsynaptic - affecting nicotinic ACh receptors
23
Q

What are the 2 mechanisms by which drugs can affect neurotransmitter synthesis?

A
  1. Production of false NT - TEC + Acetyl CoA = ATEC
  2. Choline uptake carrier blocker
24
Q

Describe the action of HEMICHOLINIUM

A

Hemicholinium binds to choline uptake carrier - preventing the uptake of choline

This decreases [choline] inside the cell = dec [ACh]

25
Q

What is Hemicholinium

A

A choline uptake carrier blocker

26
Q

What are the 2 mechanisms by which drugs can affect transmitter release (at the presynaptic site)?

A
  1. Inhibiting release
  2. Potentiating release
27
Q

Name 4 things which can be used to inhibit NT release

A
  1. Local anaesthetics
  2. Divalent cations (Mg, Zn, Cd, Co, Mn)
  3. Toxins - Botulinum toxin, beta-bungarotoxin, tetrodotoxin
  4. Aminoglycoside antibiotics - streptomycin, neomycin, kanamycin
28
Q

What can be used to potentiate release of NTs?

A

K+ channel blockers - Tetraethylammonium (TEA), 4-Aminopyridine

29
Q

How do local anaesthetics inibit release of NT?

A

Block Na+ channels in presynaptic nerve
Stop generation of AP
Preventing release of NT

30
Q

How do Divalent cations inhibit NT release?

A

Block presynaptic Ca2+ channels
Stopping release of ACh

31
Q

How does Botulinum toxin work?

A

Enters nerve terminal on presynaptic side
Proteases destroy part of the nerve terminal where vesicles fuse

32
Q

Where does beta-bungarotoxin in come from ?

A

Snake venom (krait)

33
Q

How does beta-bungarotoxin inhibit release of NT?

A

Destroys pre-synaptic nerve terminals

34
Q

How does botulinum toxin inhibit release of NT?

A

Proteases destroy part of the nerve terminal where vesicles fuse

35
Q

How does tetrodotoxin inhibit release of NT?

A

Blocks Na+ channels which prevents ALL generation of APs

36
Q

How do K+ channel blockers potentiate release of NT?

A

Cause the prolonged duration of action potential - increasing release of NT (due to inc Ca2+)

*used in the treatment of MS

37
Q

What are the targets at the synapse for LAs and divalent cations?

A

Local anaesthetics - Na+ channels

Divalent cations - Ca2+ channels

38
Q

What are the targets at the synapse for aminoglycoside antibiotics?

A

Ca2+ channels

39
Q

How does affecting the EPP affect transmission?

A

Decreasing EPP below threshold = transmission failure

Increasing EPP above threshold = transmission success

40
Q

How can we increase the possibility of neurotransmission during periods of reduced ACh release? (2 ways)

A
  1. ACh inhibitors - inc [ACh]
  2. K+ channel blockers - prolong depolarisation / delay repolarisation - therefore increase the duration of the AP
41
Q

What do you call drugs that affect neurotransmission at the postsynaptic site?

A

Neuromuscular blockers

42
Q

What do neuromuscular blockers do?

A

Affect neurotransmission at the postsynaptic site

43
Q

What are the 2 types of neuromuscular blocker / muscle relaxant?

A

NDC & DNC

  1. Non-depolarising, competitive blockers - NDC
  2. Depolarising, non-competitive blockers - DNC
44
Q

How did neuromuscular blockers (depolarising, non-competitive) revolutionise surgery?

A

Relax the muscle tone
Therefore dangerous amounts of anaesthetic don’t have to be used during general anaesthesia

*Plane 3 anaesthesia needed for surgery, but plane 4 can cause paralysis of the brain stem (and death)

45
Q

How do non-depolarising, competitive blockers work?

A
  1. Ligand gated ion channels (nicotinic ACh receptors) need 2 ACh to bind.
  2. NDCb competes with ACh for the binding site
  3. Prevent ACh binding
  4. Therefore there is less influx of Na+ into postsynaptic membrane
  5. Decreasing EPP below threshold
  6. = transmission failure (no AP generated)
46
Q

How do you reverse the action of Non-depolarising, competitive (neuromuscular) blockers?

A

Increase [ACh] by using an acetylcholinesterase inhibitor

47
Q

What do muscle relaxants do and what are they used for?

A

Relax all voluntary muscles

Major use in general surgery
*(also need artificial ventilation as they will also relax intercostal muscles & the diaphragm - preventing breathing)

48
Q

Can you reverse the synaptic block for non-depolarising blockers?

A

Yes
Increase [ACh] by using an acetylcholinesterase inhibitor
Decreases competition

49
Q

Can you reverse the synaptic block for depolarising blockers?

A

Not easily

Have to wait for the drug to be metabolised and destroyed as they cause receptor desensitisation - and therefore increasing activation of receptors is ineffective

50
Q

How do neuromuscular blockers affect the EPP?

A

Decrease the EPP

As they reduce the number of active ACh receptors

= no muscle contraction
= muscle relaxation

PHAR0002 (20 decks)

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