Neuromuscular Junction Transmission

Question 1

Review: How many muscle fibers can a neuron activate? By how many neurons is one muscle fiber activated?

Answer 1

One motor neuron innervates multiple muscle fibers.

Each fiber is only innervated by one neuron.

Question 2

What enzyme makes acetylcholine (ACh)? What is ACh made from?

Answer 2

Choline acetyl transferase. ACh is made from Acetyl CoA + choline.

Question 3

How does ACh get into vesicles?

Answer 3

An ACh/H+ exchanger.

Question 4

What are the three “stages” of ACh-containing vesicles in the pre-synaptic neuron? About how many of them are there in a resting neuron?

Answer 4

Immediate store (Primary -sitting on membrane, ready to release) - ~1000
Mobilization (can get to membrane in ~1sec) - ~10,000
Reserve - ~100,000

Question 5

What three molecules mentioned are important for vesicle fusion / ACh release? (specify if on vesicle or cell membrane)

Answer 5

On vesicle: Synaptobrevin

On cell membrane: SNAP-25 and Syntaxin

Question 6

Review: What ion induces vesicle fusion / ACh release?

Answer 6

Ca++

Question 7

How many ACh-contaiing vesicles are released in a normal calcium influx?

Answer 7

about 20% of the immediate store -> ~200

Question 8

What is Lambert-Eaton Myasthenia?

Answer 8

An autoantibody inhibits Ca++ channels in the pre-synaptic motor neuron and causes reduced ACh release.

Question 9

How does muscle contraction get turned off? (2 ways)

Answer 9

Acetylcholinesterase breaks down ACh.

ACh is moved back into pre-synaptic neuron by Na+/ACh cotransporter.

Question 10

How many molecules of ACh do you need to activate AChR?

Answer 10

2. (but this is probably trivia)

Question 11

Are there different fetal and adult ACh receptors?

Answer 11

Yes.

Question 12

What happens if you get autoantibodies against MuSK?

Answer 12

Because MuSK is in a complex with AChR, antibodies against MuSK produce Myasthenia Gravis (which we learned about previously as Abs against AChR).

Question 13

What enters the muscle cell when AChR ion channels are opened?

Answer 13

Na+

Question 14

What happens when the threshold voltage is reached in muscle cells?

Answer 14

V-gated Na+ channels open -> AP -> contraction

Question 15

How is the Safety Factor calculated?

Answer 15

End plate potential - (-50mV) = Safety factor

End plate potential must exceed -50mV in order to cause an AP in the muscle cell.

Question 16

What is the CMAP?

Answer 16

Compound Muscle Action Potential - the sum of muscle action potentials detected with EMG

Question 17

If you have impaired NMJ, what does your CMAP look like?

Answer 17

CMAP decreases with time, but levels off at about 1 second, when secondary ACh vesicles are utilized.

Question 18

Who gets Lambert-Eaton Myasthenic Syndrome?

Answer 18

1/3: People with other autoimmune disease

2/3: People with squamous cell carcinoma

Question 19

What part of a patient’s history would make you suspect an NMJ disorder?

Answer 19

Fluctuating symptoms: weakness that gets better or worse with use. (yes, many other things would make you suspicious, but go with it…)

Question 20

Would you suspect and HMJ if a patient reported numbness?

Answer 20

No, because that would suggest that sensory nerves are involved as well.

Question 21

How do botulinum toxin work?

Answer 21

Proteases that cleave SNAP-25 or Syntaxin on the pre-synaptic membrane -> no ACh release -> flaccid paralysis.

Question 22

Contrast botulinum toxins with C. tetani toxins.

Answer 22

Tetanus toxin targets synaptobrevin, but acts on inhibitory axons in the spinal cord -> muscle contraction. Tetanus toxin doesn’t act at the NMJ.

Question 23

How do organophosphorous gases kill you?

Answer 23

Activate V-gated Na+ channels on the muscle -> muscle depolarizes and can’t repolarize to produce APs -> paralysis. Paralysis of the diaphragm prevents breathing -> death.

Question 24

What do physostigmine, neostigmine, and pyridostigmine do?

Answer 24

The -stigmine drugs (are broken down by acetylcholinesterase to metabolites that) inhibit acetylcholinesterase -> increased ACh in the NMJ. Good for things like myasthenia gravis.

Question 25

Aside from auto-Abs directly blocking AChR in myasthenia gravis, how else do the Abs cause disease?

Answer 25

Abs -> inflammation -> reduced number of AChR molecules on and damage to the motor end-plate.

Question 26

How do paralytics such as succinylcholine work?

Answer 26

Bind to AChR and keep in open -> Na+ comes in and depolarizes cell. Cell stays depolarized, no APs -> flaccid paralysis. (note it causes an initial contraction)

Question 27

What is pancuronium? How does it work?

Answer 27

Paralytic used in surgery. Competitive inhibitor of AChR.