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BS22001 Human physiology and pharmacology > 12. NMJ > Flashcards

12. NMJ Flashcards

1
Q

How fast can action potentials travel?

A

up to 120 metres/sec

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2
Q

Where are action potentials triggered?

A

The pre-synaptic nerve terminal, release of neurotransmitters during excitation

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3
Q

What do neurotransmitters acting on receptors on the post-synaptic neuron cause?

A

Excitation or inhibition (excitation in this case)

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4
Q

How many neurons in the Human brain?

A

100 billion neutrons with 1000+ synapses resulting in 100 trillion interconnections

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5
Q

What is the synapse?

A

where communication occurs via the release of neurotransmitters from pre-synaptic nerve terminals to act upon receptors on the post-synaptic membrane

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6
Q

What is the role of a vesicle?

A

to store and protect the neurotransmitter and fuse with pre-synaptic membrane during exocytosis

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7
Q

List the 5 steps of synaptic transmission

A
  1. Synthesis- of the transmitter using enzymes
  2. Storage - via vesicles to protect and package/concentrate transmitter
  3. Release - action potential generated - depolarisation- Ca2+ increase - exocytosis
  4. Activation - post synaptic receptors activated.
  5. Inactivation
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8
Q

How do drugs enhance synaptic transmission?

A

Direct stimulation or indirect action

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9
Q

How do drugs inhibit synaptic transmission?

A
  1. blocking the synthesis, storage and release of the neurotransmitter from the pre-synaptic neuron
  2. blocking post-synaptic receptors
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10
Q

Drugs acting directly on receptors can be divided into…

A

Agonists - activate

Antagonists - block

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11
Q

What is an Agonist?

A

drugs, hormones or transmitter which bind to specific receptors and initiate a conformational change resulting in a biological response

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12
Q

What is Affinity?

A

the ability of an agonist to bind to receptors

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13
Q

What is Efficacy?

A

the ability of an agonist once bound, to initiate a response

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14
Q

Name 2 steps of the activation of receptors by agonists

A
  1. Binding step (affinity)

2. Activation step (efficacy)

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15
Q

What is an antagonist?

A

bind to the receptor and prevents the agonist from initiating a biological response

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16
Q

Do antagonists possess Affinity and Efficacy for their receptor?

A

antagonists possess affinity but not efficacy as they block receptor activation by the agonist and therefore block the effect of the agonist.

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17
Q

Describe the role of a competitive agonist and how is its effect blocked?

A
  • to compete with the agonist for the receptor binding site.

- block is reversed by increasing agonist concentration

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18
Q

What is the transmitter of interest? and what classification is the transmission?

A

Acetyl choline via cholingeric transmission

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19
Q

What are the 2 classes of cholinoceptors? and what are these activated by?

A
  1. nicotinic cholinoceptors - activated by acetyl choline or nicotine (but not muscarine)
  2. Muscarinic cholinoceptors - activated by acetyl choline or muscarine (but not nicotine)
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20
Q

What is fast synaptic transmission mediated by? give an example and state their role.

A

mediated by transmitter-gated ion channels
- e.g. nAChR (nicotinic acetyl choline receptor) which conduct potassium ions, high conc sodium ions outside of the cells and low conc inside the cell.

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21
Q

State characteristics of transmitter-gated ion channels

A
  • integral ion channels
  • agonist binding to the receptor induces a rapid conformational change to open the channels
  • channel is selective for certain ions
  • signalling is rapid (milliseconds)
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22
Q

What is electrophysiology?

A

used to record synaptic transmission at the NMJ.

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23
Q

What is intracellular recording?

A

records mepps and uses electrodes to record the voltage at the NMJ.

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24
Q

Describe the events which occur after the release of acetyl choline from a single vesicle

A
  • acetyl choline is released from a single vesicle
  • activation of many nicotinic acetyl choline receptors
  • upon activation, nicotinic cation channels open and Na+ ions flux into the muscle fibre
  • depolarisation of the end-plate potential
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25
Q

What molecule can influence spontaneous transmitter release

A

a-LTX (black widow spider venom)

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26
Q

What is exocytosis?

A

vesicle fusion

27
Q

What is endocytosis?

A

recovery of the vesicular membrane after fusion

28
Q

How do you see the effects of the toxin?

A

Control conditions
1. record mepps before and after the release of the toxin
2. electron microscopy pictures at random intervals
after; depletion of vesicles inhibition of endocytosis and distended terminal paralysis

29
Q

Give the steps of a simplified model of fast synaptic transmission

A
  1. pre-synaptic action potential
  2. a synchronous Ca2+ influx via voltage-gated ion channels
  3. many vesicles undergo exocytosis releasing a large cloud of acetylcholine
  4. Activation of many nicotinic receptors
  5. Causing a large depolarisation of the end-plate region of the muscle cell (goes from a negative to positive state)
  6. if depolarisation is large enough, it activates post-synaptic voltage-gated sodium channels to fire an action potential
30
Q

Why is signalling of nicotinic receptors faster than that of muscarinic receptors?

A

nicotinic receptors are ion channel receptors which are faster than muscarinic receptors which are g-protein coupled receptors as signalling takes milliseconds as opposed to the g-protein coupled receptor which takes minutes.

31
Q

what information about nicotinic receptors can be obtained using the patch-clamp technique?

A

it can be used to measure the current which passes through an ionic channel and the membrane potential of active cells.

32
Q

Why are calcium and magnesium essential for neurally-evoked neurotransmitter release?

A

calcium triggers vesicle fusion and magnesium blocks the voltage-gated calcium ion channels

33
Q

Name a technical issue when studying the neuromuscular junction and how can this issue be resolved?

A

when studying the NMJ, nerve stimulation causes muscle contraction which can result in the glass micro electrode breaking. Therefore use a high magnesium/ low calcium buffer solution.

34
Q

What does a high magnesium/low calcium buffer solution resolve this issue?

A

it reduces the EPP to below threshold and so no firing of the action potential. Less calcium will mean less vesicle fusion and so results in an average decrease in size of EPP.

35
Q

What is Quantal content? how can it be calculated?

A

Number of vesicles per nerve stimulus and can be calculated by dividing the mean EPP amplitude (mV) by the mean MEPP amplitude (mV).

36
Q

What do you understand about the terms; miniature end-plate potential (repps) and end-plate potential?

A

Mepps - are small depolarisations of the post-synaptic terminal caused by the release of a single vesicle into the synaptic cleft.
Epps - voltages which cause depolarisations of the skeletal muscle fibre when a neurotransmitter binds to a receptor on the post-synaptic membrane.

37
Q

Describe how Mepps and Epps are produced

A

neurotransmitters are packaged into vesicles called quanta. one quanta is released into the synaptic cleft, generating a Mepp via activation of the nicotinic receptor (the smallest amount of stimulation one neuron can send to another). Mepps come together to form Epps.

38
Q

What causes Mepps and Epps?

A

Mepps occur spontaneously whereas Epps occur in response to motor nerve stimulation.

39
Q

How does a pre-synaptic action potential produce an action potential in the post-synaptic region of the muscle fibre?

A

an action potential is generated in the pre-synaptic neuron which binds about exocytosis- where the vesicle fuse with the pre-synaptic membrane and release neurotransmitters into the synaptic cleft. The neurotransmitters bind to receptors on the post-synaptic membrane which makes the cell more or less likely to fire an action potential

40
Q

How is acetyl choline synthesised?

A

by the reaction of acetyl coenzyme A and choline using the enzyme choline acetyl transferase.

41
Q

What can effect the steps involved in the release of neurotransmitters?

A

Drugs and toxins

42
Q

How does the toxin Tetrodotoxin cause muscle paralysis?

A

it blocks Na+ channels. meaning there is no action potential produced and so no release of neurotransmitters. No Epps are produced causing muscle paralysis, leading the respiratory failure.

43
Q

How does the toxin Conotoxin cause muscle paralysis?

A

it blocks calcium channels and so no release of neurotransmitters causing a decrease in QC

44
Q

How does the toxin Dendrotoxin cause muscle paralysis

A

it blocks potassium channels so prolonged action potential, increases calcium influx and increase in release of neurotransmitters. This increases the EPP and MEPP amplitude and increases QC

45
Q

How does the toxin Botulinium toxin cause muscle paralysis?

A

it blocks vesicle fusion by cleaving vesicular protein required for exocytosis and therefore decreases release. EPP amplitude decreases but no change to MEPP amplitude so QC decreases.

46
Q

What drugs cause skeletal muscle relaxation?

A

tubocurarine, a-bungarotoxin and suxxamethonium

47
Q

What do these drugs interact with to produce this paralysis?

A

nicotinic acetyl choline receptors

48
Q

What type of molecule is Tubocurarine?

A

competitive nicotinic receptor antagonist and a non-depolarising neuromuscular blocker

49
Q

What is a competitive antagonist?

A

a molecule which binds to the agonist binding site on the receptor and blocks activation

50
Q

What do non-depolarising neuromuscular blockers do?

A

they compete with acetyl choline for binding to the nicotinic receptors. in the presence of these, acetyl choline is still released, but there are fewer receptors available.

51
Q

What does the effect of non-depolarising blockers have on the NMJ?

A

reduces depolarisation so reduces the EPP amplitude to below threshold for firing an action potential and therefore causes the muscles to relax.

52
Q

How can the effects of Tubocurarine be reversed?

A

Neostigmine - favours acetyl choline over Tubocurarine and so reverses neuromuscular block.

53
Q

What is the clinical use of Tubocurarine?

A

used by surgeons to cause skeletal muscle relaxation to prevent unwanted contractions during surgery.

54
Q

What is neostigmine?

A

an anticholinesterase which works to decrease the breakdown of acetylcholine

55
Q

What does a-bungarotoxin do?

A

it binds close to the agonist binding site on cholingeric receptors blocking their activation and causing skeletal muscle paralysis.

56
Q

What effect does a-bungarotoxin have on QC?

A

it decreases the amplitude of EPP and MEPP and so no change in QC

57
Q

Is the effect of a-bungarotoxin blocked by washing or neostigmine?

A

no- because it is bound irreversibly to the receptor

58
Q

What molecule is the drug Suxamethonium?

A

a selective nicotinic receptor agonist - mimic the action of acetyl choline. it is also a depolarising blocker

59
Q

How do depolarising blockers act?

A

they are not broken down by acetyl co-A and choline and so has a prolonged time in the synaptic cleft. It can then reactivate receptors and repetitively bind causing a prolonged depolarisation. This causes the voltage-gated sodium channels to go into an inactive state known as phase 1 block.

60
Q

What are the steps which cause a phase 1 block?

A
  1. persistant activation of the end-plate nicotinic receptors
  2. prolonged depolarisation of the end-plate
  3. inactivation of voltage-gated sodium ion channels
61
Q

what are the steps which cause a phase 2 block?

A
  1. pre-sensitisation of nicotinic receptors
  2. repolarisation of endplate
  3. receptor desensitisation maintains blockade
62
Q

What happens during the inactivation stage?

A

acetyl choline is broken down into the inactive metabolites choline and acetate by acetylcholinesterase.

63
Q

Types of cholinesterase

A
  1. “TRUE” acetylcholine esterase (AChE)

2. pseudo-cholinesterase

BS22001 Human physiology and pharmacology (9 decks)

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