Peter's Physiology

Question 1

Skeletal muscle is innervated by what type of neurones?

Answer 1

Alpha-motor neurones

Question 2

Where are the cell bodies of alpha-motor neurones found? (2)

Answer 2

Spinal cord

Brainstem

Question 3

The whole of the alpha-motor neurone is myelinated. T/F

Answer 3

False

Axons are initially myelinated but then become unmyelinated when they branch to supply individual muscle fibres

Question 4

What is a motor unit?

Answer 4

The alpha-motor neurone and all of the skeletal muscle fibres that it innervates

Question 5

Describe the structure of the axon branch which branches from a motor neurone axon to supply a single muscle fibre

Answer 5

• Unmyelinated

- Divides into multiple fine branches that end in a terminal bouton

Question 6

Describe the structure of the axon branch which branches from a motor neurone axon to supply a single muscle fibre

Answer 6

• Unmyelinated

- Divides into multiple fine branches that end in a terminal bouton

Question 7

What is the function of the terminal bouton of motor neurones? (2)

Answer 7

• Forms a chemical synapse with the muscle membrane at the neuromuscular junction
• AP’s in the cell body are conducted to cause ACh release

Question 8

Describe the structure of the skeletal NMJ, making reference to the…

• Terminal bouton
• Synaptic vesicles
• Synaptic cleft
• The end plate region on the muscle cell membrane
• Nicotinic ACh receptors (nAChRs)

Answer 8

• Terminal bouton sits in close apposition with the muscle cell membrane
• Synaptic vesicles containing ACh line up in active zones inside the terminal bouton and await release when an AP arises
• Synaptic cleft is the space between the terminal bouton and the end plate region of the muscle cell membrane that ACh will cross
• The end plate region of the muscle cell membrane is thrown into a series of junctional folds
• nAChRs are found in regions of the junctional folds that face the active zones

Question 9

Outline the synthesis, storage and exocytotic release of ACh

Answer 9

• ACh is synthesised from choline and acetyl CoA (by choline acetyltransferase) in the cytoplasm of the terminal bouton
• ACh is taken up into synaptic vesicles by the vesicular ACh transporter for concentration and storage
• ACh is released into the synaptic cleft by Ca2+-dependent exocytosis when an AP opens voltage-gated Ca2+ channels

Question 10

What happens to ACh once it is exocytosed? (2)

Answer 10

• Briefly activates nicotinic ACh receptors (nAChRs) on the end plate region by reversibly binding to them
• Action rapidly terminated by acetylcholinesterase (AChE), which breaks ACh down in the synaptic cleft

Question 11

Describe the structure of nicotinic ACh receptors (nAChRs)

Answer 11

• Made of 5 glycoprotein subunits
• Have 2 ACh binding sites
• Central cation selective pore allows for Na+ influx and K+ efflux when ACh binds

Question 12

How does activation of nAChRs cause a depolarising (+ve) end plate potential (e.p.p.)?

Answer 12

Na+ influx is greater than K+ efflux

Question 13

What is meant by the ‘quantum nature’ of ACh release?

Answer 13

• Each vesicle of ACh contains a ‘quantum’ of neurotransmitter that can cause a miniature end plate potential (m.e.p.p.)
• The e.p.p. is the summation of many m.e.p.p.’s due to many vesicles being released

Question 14

How does e.p.p. initiate an AP in the muscle cell?

Answer 14

If the e.p.p. generated by the summation of the m.e.p.p.’s is sufficient to cross the threshold for opening of voltage-gated Na+ channels (+50mV), an AP is produced

Question 15

Why is the muscle action potential required for muscle contraction, not just the e.p.p.?

Answer 15

• nAChRs at the muscle cell membrane mediate the e.p.p., which will wane as it spreads away from the endplate
• Voltage-gated Na+ channels will open along the muscle membrane and so can maintain the upstroke of the AP along the length of the muscle fibre

Question 16

How does the muscle AP cause contraction?

Answer 16

AP arrival at T-tubules in the sarcoplasmic reticulum results in Ca2+ release from the SR lateral sacs

Ca2+ interacts with troponin to allow the actin-myosin cross-bridge to form

Question 17

Why is there a delay between muscle AP and peak muscle contraction?

Answer 17

Time is required for Ca2+ to be released from the SR and cause cross-bridge formation

Question 18

Why does a long relaxation period occur following muscle contraction?

Answer 18

Time is required for Ca2+ to unbind from troponin and be reabsorbed into the SR

Question 19

Describe how acetylcholinesterase (AChE) terminates the action of ACh

Answer 19

AChE rapidly hydrolyses ACh into choline and acetate (sometimes even before it can bind to nAChRs)

Question 20

What is the fate of choline and acetate in the synaptic cleft?

Answer 20

Choline is taken up by the sodium-choline transporter on the pre-synaptic neurone

Acetate diffuses from the synaptic cleft as an inactive metabolic byproduct

Question 21

How do anti-cholinesterases work?

Answer 21

These are therapeutics that reversibly block the action of AChE to allow more ACh to be active in the synaptic cleft

Question 22

List 3 clinical conditions in which transmission at the NMJ is defective

Answer 22

• Neuromyotonia
• Lambert-Eaton-Myasthenic Syndrome (LEMS)
• Myasthenia Gravis (MG)

Question 23

List 2 medical treatments that interfere with transmission at the NMJ

Answer 23

• Botulism

- ‘Curare-like’ compounds

Question 24

What is myasthenia gravis and how does it arise?

Answer 24

• An autoimmune disease with progressive worsening of muscle weakness with activity
• Arises as auto-antibodies target nAChRs and so they are reduced in number, resulting in a lower e.p.p. and less AP generation

Question 25

What is neuromyotonia and how does it arise?

Answer 25

• An autoimmune disease with hyperexcitability of motor neurones and repetitive firing to skeletal muscle fibres
• Arises as auto-antibodies target voltage-gated K+ channels in the motor neurone

Question 26

What is Lambert-Eaton Myasthenic Syndrome (LEMS) and how does it arise?

Answer 26

• An autoimmune disease associated with small cell lung cancer and characterised by muscle weakness in the limbs
• Arises as auto-antibodies target voltage-activated Ca2+ channels, reducing Ca2+ entry into the motor neurone and therefore ACh release is also reduced

Question 27

How does the botulinum toxin act on the body?

Answer 27

It acts at motor neurone terminals to irreversibly inhibit ACh release, causing muscle paralysis

Question 28

How do ‘curare-like’ compounds act in the body?

Answer 28

They act as competitive antagonists of the nAChRs which reduces the e.p.p. to below the threshold for muscle AP generation

Question 29

When are botulinum toxins and ‘curare-like’ compounds used clinically?

Answer 29

Low dose botulinum toxins: to treat over-active muscles (e.g., eyelids) or to smooth out wrinkles

Curare-like compounds: used in surgery to produce reversible paralysis