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BS22001 > Neuromuscular Junction > Flashcards

Neuromuscular Junction Flashcards

1
Q

Synapses

A

communication occurs via the release of chemical messengers (neurotransmitters) from presynaptic nerve terminals to act upon receptors on the postsynaptic membrane

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2
Q

Neuromuscular junction

A

synapse between neurone and a skeletal muscle fibre

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3
Q

Synaptic transmission at the neuromuscular junction

A

the release of transmitter onto receptors involves 5 steps, each of which can be affected by drugs and toxins resulting in either an increase or decrease in transmission

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4
Q

5 steps of synaptic transmission

A
  1. synthesis of the transmitter from a precursor and an enzyme
  2. storage of transmitter
    - protect
    - package (quanta)
  3. transmitter released by vesicular exocytosis
  4. activation by binding of transmitter to receptors
  5. transmitter reaches inactivating enzyme and there is an uptake of transmitters
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5
Q

Drugs can enhance synaptic transmission by

A 
Direct stimulation of post-synaptic receptors by
- the natural transmitter
- analogues
Indirect action via
- increased transmitter release
- inhibition of transmitter removal
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6
Q

Drugs can inhibit synaptic transmission by

A
  • blocking synthesis storage or release from the presynaptic neurone
  • blocking postsynaptic receptors
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7
Q

Drugs acting directly on receptors (types)

A

agonists and antagonists

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8
Q

Agonists

A
  • drugs, hormones or transmitters which bind to specific receptors and initiate a conformational change in the receptor resulting in a biological response
  • affinity and efficacy
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9
Q

Affinity

A

the ability of agonists to bind to receptors

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10
Q

Efficacy

A

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

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11
Q

What is the neurotranmitter at the NMJ?

A

acetylcholine

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12
Q

Activation of receptors by agonists

A
  • an agonist binds with a receptor to produce an agonist/receptor complex
  • the receptor is ligand-specific and so is like a ‘lock and key’
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13
Q

Binding step (agonists)

A

Agonist + receptor

- affinity

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14
Q

Activation step (agonists)

A

complex –> response

- efficacy

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15
Q

Antagonists

A

Antagonist + receptor -> complex

  • affinity
  • antagonists bind to receptors but do not activate them
  • possess affinity but lack efficacy
  • antagonists block receptor activation by agonists
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16
Q

Competitive nicotinic receptor antagonists

A

competes with the agonist for the agonist binding site on the receptor; block is reversed by the increase in agonist concentration

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17
Q

How are synapses classified?

A
  • according to the transmitter released from the presynaptic neurone
  • for synapses where the presynaptic neurone synthesises and released ACh transmission = cholinergic
  • receptors which ACh acts on are called cholinoceptors
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18
Q

Types of cholinoceptors

A

Nicotinic
- activated by ACh or nicotine but not muscarine
Murcarinic
- activated by ACh or muscarine (fungal alkaloid( but not nicotine

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19
Q

What is the nicotinic ACh receptor?

A

a transmitter-gated ion channel

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20
Q

Transmitter-gated ion channels

A
  • integral ion channel
  • agonist binding to the receptor induces a rapid confrormational change to open the channel
  • the channel is selective for certain ions
  • signalling is extremely rapid (milliseconds)
  • consist of seperate protein subunits that form a central, ion conducting, channel
  • allow rapid changes in the permeability of the membrane to certain ions
  • rapidly alter membrane potential
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21
Q

What does ACh released from a vesicle cause?

A
  • a miniature endplate potential (MEPP)
  • it activates many nicotinic ACh receptors
  • upon activation the associated nicotinic cation channels open and Na ions flux into the muscle fibre to cause a local depolarisation at the endplate region
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22
Q

Synaptic transmission at the neuromuscular junction

A
  • motor nerve stimulation causes synchronous release of many vesicles; summation of mepps to produce an epp
  • membrane potential is negative
  • MEPP molecules depolarise past the threshold
  • this causes voltage gates Na channels to open
23
Q

Quantal content

A
  • number of vesicles/stimulus
  • QC = (mean EPP amplitude (mV) / (mean MEPP amplitude (mV)
  • each quanta gives rise to a miniature end plate potential (mepp) via activation of nicotinic ACh receptors
24
Q

When do mepps occur?

A

spontaneously

25
Q

When do epps occur?

A

in response to a motor nerve stimulation

26
Q

What happens when mepps summate to give an epp?

A

Initiates an action potential which causes muscle contraction

27
Q

Cholinergic transmission and the NMJ

A
  • choline acetyl transferase (CAT) synthesises ACh from precursors choline and AcE A from mitochondria
  • Re-uptake of choline is Na dependent and blocked competitively by hemicholinium 3
  • there will be less ACh in each vessicle
  • amplitude f the epp and mepp both decrease
28
Q

Tetrodotoxin (TTX)

A
  • blocks Na channels (no action potential, no release, no EPP)
29
Q

Conotoxin

A
  • blocks voltage-gated Ca channels
  • a decrease in calcium influx decreases the release
  • the epp amplitude decreases, no change in mepp amplitude
  • decreased quantal content
30
Q

Dendrotoxin

A
  • blocks voltage-gated K channels
  • prolonged action potential
  • increased calcium influx causes an increase in release
  • increased epp amplitude
  • no change in mepp amplitude
  • increased quantal content
31
Q

Botulinum toxin

A
  • blocks vesicle fusion
  • no release
  • EPP amplitude decreases
  • MEPP amplitude doesn’t change
  • quantal content decreases
32
Q

Quantal content calculation

A

QC = EPP amplitude (mV)/MEPP amplitude (mV)

33
Q

If tubocurarine has a decrease in EPP and decrease in MEPP, how will this effect the QC?

A

no change

34
Q

If tubocurarine has an increase in EPP and decrease in MEPP, how will this effect the QC?

A

increase

35
Q

If tubocurarine has a decrease in EPP and increase in MEPP, how will this effect the QC?

A

decrease

36
Q

Non-depolarising neuromuscular blockers

A
  • compete with ACh for binding to skeletal muscle nicotinic ACh receptors
  • reduce the amplitude of the EPP to below the threshold for muscle fibre action potential generation
  • block Na from leaving the cell
37
Q

Tubocurarine

A
  • used during surgery to produce skeletal muscle relaxation
  • competitive non-depolarising neuromuscular blocking agent
  • muscle block reversed by anticholinesterases e.g. neostigmine
  • from the plant curare
38
Q

Bungarotoxin

A
  • snake venom from Taiwan Banded Krait

- not reversed by washout or by anticholinesterases

39
Q

Suxamethonium

A
  • a skeletal muscle relaxant
  • rapid onset (30s) and short duration (5 min) of action
  • used in ECT and for rapid tracheal intubation
  • metabolised by PLASMA (butyryl cholinesterase)
  • 1 in 3000 individuals express a genetic variant of the enzyme that does not degrade suxamethonium, causing a prolonged blockade
40
Q

Skeletal NMJ depolarising blockers (suxamethonium)

A

Phase I block:

  • persistent activation of endplate nicotinic receptors
  • prolonged depolarisation of endplate
  • inactivation of voltage-gated sodium channels

Phase II block

  • desensitisation of endplate nicotinic receptors
  • repolarisation of endplate
  • receptor desensitisation maintains blockade
41
Q

Pharmacology of ACh and nicotine

A

agonist

42
Q

Pharmacology of suxamethonium

A

agonist

43
Q

Tubocurarine

A

competitive antagonist

44
Q

a-Bungarotoxin

A

irreversible antagonist

45
Q

Cholinergic transmission and the NMJ (inactivation)

A
  • ACh is terminated by acetylcholinesterase (AChE), which breaks down ACh to acetate and choline
  • drugs which inhibit AChE anticholinesterases (e.g. nerve gases, neostigmine) increase the effects of ACh
46
Q

True acetylcholinesterase (AChE)

A
  • present at cholinergic synapses

- bound to the postsynaptic membrane in the synaptic cleft

47
Q

Pseudo-cholinesterase (butyrylcholinesterase or plasma cholinesterase)

A
  • widely distributed and found in plasma
  • important in inactivating the depolarising neuromuscular blocker, suxamethonium
  • both ‘true’ and pseudo cholinesterases are inhibited equally by most clinically-relevant anticholinesterases
48
Q

Anticholinesterases (clinical uses)

A
  • used to reverse non-depolarising skeletal muscle relaxants e.g. tubocurarine
49
Q

Anticholinesterases and QC

A
  • anticholinesterases such as neostigmine increase the amplitude of the EPP and MEPP
  • no effect on QC
  • neostigmine prolongs the duration of the mepp and epp due to the increased ‘life-time’ of ACh in the synaptic cleft which permits receptor rebinding
50
Q

Anticholinesterase treatment of Myasthenia Gravis

A
  • auto-immune disease
  • loss of NMK nACh receptors
  • muscular weakness, paralysis
  • reversed by inhibitor of AChE e.g. treatment with neostigmine, diagnose with edrophonium
51
Q

Anticholinesterases (organophosphates) as Nerve Gas Agents

A
  • binds very stably
  • recovery requires synthesis of new enzyme (weeks)
  • dyflos: volatile, non-polar, lipid soluble, rapidly absorbed through mucous membranes and unbroken skin & cross the blood brain barrier
52
Q

Reversal of organophosphate nerve gas

A

Atropine
- counteract effects of excessive muscarinic receptor stimulation by ACh
Oximes
- e.g. pralidoxime (2-PAM) antidote to Nerve Gas reactivates the AChase

53
Q

Organophosphates as insecticides

A

Readily absorbed through the insect cuticle

BS22001 (2 decks)

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