Neuromuscular Transmission and drugs

Question 1

neuromuscular junction definition

Answer 1

Chemical synapse formed by the contact between a motor neurone and a muscle fibre

Question 2

Structure of neuromuscular junction

Answer 2

• terminal region of motor neurone has no myelin sheath
• presynaptic neurone formed of a synaptic knob
• contains calcium ion channels
• synaptic cleft separates the axon from the muscle fibre
• sarcolemma at the junction has postjunctional folds to increase the surface area for neurotransmitter release

Question 3

What is a motor end plate?

Answer 3

The region of the muscle fibre innervated by one nerve

Question 4

Process of sending an impulse across the NMJ

Answer 4

1. action potential depolarises motor axon
2. depolarisation opens voltage gated calcium channels in the terminal membrane, causing calcium ions to move in.
3. Triggers the fusion of docked synaptic vesicles
4. acetylcholine contained is released into the synaptic cleft
5. acetylcholine diffuses across the synaptic cleft and binds to the nicotinic receptors on the muscle fibre
6. non selective cation channels open and depolarises the membrane in the end plate region
7. when threshold is reached, an action potential is generated

Question 5

What is an EPP?

Answer 5

End plate potential- depolarisation of the muscle region

Question 6

Synthesis of ACh explained

Answer 6

Synthesised by enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. High uptake of choline from synaptic cleft, often achieving Vmax

Question 7

How is ACh moved into vesicles?

Answer 7

vesicular ACh transporters uptake ACh using an ATPase.

Question 8

Release of ACh explained

Answer 8

V-snares bound to the transport vesicles, T-snares present on the cell membrane.

The V and T snares fuse to form a trans-snare complex (snare pin) that allow the acetylcholine to be released.

Release in quanta- each vesicle contains roughly 4 units of ACh

Question 9

4 snare proteins involved and function

Answer 9

V snare- present on vesicle. Bind to t snares and form trans snare complex.

T snare- present on membrane, bind to v snares to form trans snare complex

Q snare- synaptobrevin and R snare, syntaxin along with V and T assemble to form core snare complex.

Question 10

What is the process of zippering?

Answer 10

Fusion of V and T thought to lead to a conformational change of the trans snare complex to cis snare complex.

Released energy thought to cause molecular bending stress in the snare motifs and causes mechanical stress.

the energetically unfavourable bending is overcome by the two membranes fusing

Question 11

ACh action explained

Answer 11

Binds to nicotinic receptors on end plate, which are ligand gated channels and open them. Binds to two cysteine residues forming a specific cys-loop receptor

Question 12

What happens once ACh is used?

Answer 12

Enzyme acetylcholinesterase, present in the synaptic cleft, hydrolyses the acetylcholine to choline and acetate

Question 13

Two types of neuromuscular blocking drug + definitions

Answer 13

Depolarising blocking agents- agents that depolarise the sarcolemma persistently which makes the fibre resistant to further stimulation by ACh

Non-depolarising blocking agents- agents that act competitively to block the binding of ACh to its receptors, or blocking the inotropic effect of the ACh receptors

Question 14

Examples of non-depolarising block agents

Answer 14

Curare and Vecuronium

Question 15

How does curare work? + medical use

Answer 15

Acts as an nAChR antagonist, due to its similar quaternary amino structural motif.

Used as an anaesthetic

Question 16

How does Vecuronium work? + medical use

Answer 16

Antagonist for nAChR

Provides skeletal muscle relaxation during surgery or medical ventilation

Question 17

Examples of depolarising block agents

Answer 17

Suxamethonium

Question 18

How does suxamethonium work? + medical use

Answer 18

Competitive agonist. Binding results in the opening of the monovalent cation channel

Suxamethonium has a longer duration of action than acetylcholine

It is not hydrolysed by acetylcholinesterase

Used to cause short term paralysis as part of general anaesthesia

Question 19

Other examples of drugs

Answer 19

vesamicol, botulinum toxin, neostigmine and latrotoxin

Question 20

How does vesamicol work? medical use

Answer 20

Does not act at ACh receptor

Blocks vesicular ACh transporter that is responsible for carrying ACh into vesicles

Adenocarcinoma in lungs

Question 21

Latrotoxin function and medical use

Answer 21

Neurotoxin found in the venom of spiders. Alpha latrotoxin forms pores in the presynaptic membrane.

Permeable to calcium ions, so calcium moves in and triggers all the vesicles to exocytose

Question 22

Botulinum toxin function and medical use

Answer 22

Cleaves snare proteins, preventing the release of ACh

Used for hyperhidrosis, reduction in face wrinkles. Used to treat uncontrolled muscle spasms

Question 23

How can neuromuscular block be prevented?

Answer 23

Use anti-cholinesterases to prevent the breakdown of acetylcholine, increasing its action at the available (unblocked) nAChRs

Question 24

Example of an anti cholinesterase + medical use

Answer 24

Neostigmine
Blocks the active site of cholinesterase so the enzyme can no longer break down acetylcholine.

Used to treat Myasthenia Gravis

Question 25

Explain Myasthenia Gravis

Answer 25

Autoimmune synaptopathy - immune system generates antibodies that attack the body tissues.

Specifically attack MuSK or nAChR, preventing the formation of action potentials.

Can cause drooping eyelids, double vision, trouble talking and trouble walking.

Question 26

What replaces neuromuscular junctions in both smooth and cardiac muscle?

Answer 26

Cardiac- en passant junctions

smooth - axons with varicosities

Question 27

Explain en passant junctions

Answer 27

One neurone joins another at a place beside the axon terminal. The synapses are present at the stem of the axon. Axoaxonic

Question 28

Axoaxonic definition

Answer 28

one axon joins to another along its length

Question 29

Explain varicosities

Answer 29

Many peripheral nerves have swellings termed varicosities, from which neurotransmitter is released at varying distances from the effector cells.

No specialised post junctional structure, however neurotransmitter receptors accumulate on cell membranes close to the junctions