MSK pharma

Question 1

Skeletal muscle innervation?

Answer 1

Motorneurones with myelinated axons

• the motor neurone axon divides into unmyelinated branches which innervate an individual skeletal muscle cell (muscle fibre)
• branches further divide into multiple fine branches, each ending in a terminal bouton that forms a synapse with the muscle membrane at the neuromuscular junction

Question 2

Motor unit?

Answer 2

The neurone and the number of fibres that it innervates

Question 3

What is the neurotransmitter for skeletal muscle?

Answer 3

Acetylcholine

* APs are conducted via axon to the boutons causing release of transmitter

Question 4

End plate neuron?

Answer 4

Post-synaptic terminal after terminal bouton in neuromuscular junction

Question 5

What surrounds the terminal bouton? Where are nicotinic ACh receptors found?

Answer 5

• Schwann cell surrounds terminal bouton

* Nicotinic ACh receptors found in junctional folds

Question 6

Pre-synaptic processes at neuromuscular junction?

Answer 6

• Choline transported into terminal by choline transporter (symport with Na+)
• ACh synthesised from choline + acetyl CoA by choline acetyltranferase
• ACh stored in vesicles by vesicular ACh transporter
• AP causes depolarisation and opens voltage-gated Ca++ channels
• Ca++ allows ACh to exit vesicles via exocytosis

Question 7

Post-synaptic processes at neuromuscular junction?

Answer 7

• ACh activates nicotinic receptors
• Nicotinic receptor is Na+ and K+ channel
• When channel is open, influx of Na+ is greater than K+ so depolarisation known as END PLATE POTENTIAL is generated

Question 8

What are nicotinic ACh receptors?

Answer 8

Pentamer of glycoprotein subunits [(α1)2β1δε) surrounding a central cation selective pore

Question 9

Electrical responses to synaptically released ACh at end plate?

Answer 9

• The electrical response to one quantum of transmitter is a miniature endplate potential (m.e.p.p)
• Many m.e.p.ps summate to produce the end-plate potential (e.p.p)
• An e.p.p that exceeds threshold triggers contraction

Question 10

What is muscle action potential generated by?

Answer 10

• Voltage-activated Na+ channels in end plate

* NOT nicotinic receptors (they generate e.p.p which trigger sopening of Na+ channels)

Question 11

How do some drugs or toxins cause muscle paralysis?

Answer 11

reduce amplitude of e.p.p., does not reach threshold for opening voltage-activated Na+ channels, no muscle action potential is generated

Question 12

How muscle action potential causes contraction?

Answer 12

• AP spreads over sarcolemma of skeletal muscle and enters T tubules
• Triggers release of Ca+ from SR which causes contraction (via troponin interaction)

Question 13

What causes rapid termination of neuromuscular transmission?

Answer 13

acetylcholinesterase (AChE) - hydrolyses ACh to choline (taken up by choline transporter) and acetate (diffuses from synaptic cleft)

Question 14

Insectacides and nerve agents?

Answer 14

Block the action of AChE

Question 15

Neuromyotonia (Isaac’s syndrome) s/s? (4)
Ax?
Tx?

Answer 15

• Muscle cramps, stiffness, slow relaxation (myotonia), and muscle twitches (fasiculations)
• Ax: AUTOIMMUNE antibodies against voltage-activated K+ channels resulting in hyperexcitability (repetitive firing)
• Tx: anti-convulsants (e.g. carbamazepine, phenytoin) which block voltage-activated Na+ channels

Question 16

Lambert-Eaton Myasthenic Syndrome (LEMS) s/s? Associated with?
Ax?
Tx?

Answer 16

• muscle weakness in the limbs
• associated with small cell carcinoma of the lung
• AUTOIMMUNE antibodies against Ca2+ channels causing reduced Ca2+ following depolarization and so reduced vesicular release of ACh
• Tx: anticholinesterases (e.g. pyridostigmine) and potassium channel blockers (e.g. 3,4-diaminopyridine) which increase the concentration of ACh in the synaptic cleft

Question 17

Myasthenia gravis?
Ax?
Tx?

Answer 17

• progressively increasing muscle weakness during periods of activity - weakness of the eye and eyelid muscles is a presenting feature
• Ax: AUTOIMMUNE antibodies against nicotinic ACh receptors reduce amplitude of the e.p.p.
• Tx: anticholinesterases (e.g. pyridostigmine) and immunosuppressants (e.g. azathioprine)

Question 18

Botulinum toxin?
Comps?
Tx?
Uses of botulinum toxin? (2)

Answer 18

• Extremely potent exotoxin (related to tetanus and diptheria toxins) that irreversibly inhibits ACh release (prevent exocytosis)
• Comps = death
• Tx = anti-cholinesterases

Uses

• Low dose can treat overactive muscles (dystonias)
• Smooth out wrinkles

Question 19

Curare-like compounds? Effect? Clinical use?

Answer 19

competitive antagonists of the nicotinic ACh receptor (e.g. vecuronium, atracurium)

• Reduce amplitude of e.p.p to below threshold for muscle action potential generation
• used clinically to induce reversible muscle paralysis i.e. during surgery