4 - Green - Neuromuscular Junction

Question 1

Where does the axon make contact with the muscular fiber?

Answer 1

Neuromuscular Junction (NMY) or end-plate

Question 2

NMJ Neurotransmitter

Answer 2

Acetylcholine (ACh)

Question 3

Postjunctional Fold

Answer 3

Invagination of muscle membrane at the NMJ

Question 4

Acetylcholine Resecptor (AChR)

Answer 4

Neurotransmitter receptor present on muscle membrane at the NMJ

Question 5

What enyme breaks down ACh in the synaptic cleft?

Answer 5

Acetylcholinesterase

Question 6

Active Zones

Answer 6

Regions of presynaptic membrane where synaptic vesicles fuse and release ACh

Oriented directly over post synaptic clefts

Highest density of AChRs at crests of post junctional folds

Question 7

What occurs once motor neurons release ACh?

Answer 7

ACh binds to AChR’s on the muscle membrane

Activates Voltage-Gated Na+ Channels

Na⁺ enters cell, K⁺ exits = Depolarize (move towards E_Na)

Action Potential! Muscle Contracts!

Acetylcholine broken dowon by ACh’Esterase

Question 8

How can current generation at the NMJ be measured?

Answer 8

Electromyography (EMG)

Question 9

What does the fusion of synaptic vessicles require?

Answer 9

Ca²⁺ dependent channels drive fusion

Question 10

Once sodium (Na⁺) enteres the channel what is the current generated called?

Answer 10

End-Plate Current (EPC)

Question 11

What is the result of EPC on voltage?

What is this change in potential called?

Answer 11

Becomes more positive (depolarize)

End-Plate Potential (EPP)

Question 12

When when not stimulated, what are changes in muscle membrane potential called?

What causes this?

Answer 12

Miniature End Plate Potentials (MEPPs)

Look like EPPs, but much smaller

Caused by spontaneous release of quanta of ACh

Question 13

Safety Factor

Why is this important?

Answer 13

Difference between actual EPP and threshold potential required to generate action potential

“Buffer Region”

ACh stores are not unlimited, this region ensures repetitive stimulat can still generat action potentials

Question 14

What else can bind to AChRs (their other name…)

What is their general structure?

Answer 14

Nicotine

Nicotinic AChRs

5-subunit protein, creating a central pore

Question 15

Are adult and embryonic nicotinic AChR’s the same?

Answer 15

No, embryonic has delta subunit, adult has epsilon subunit

Embryonic: Longer Open, Lower Current

Adult: Shorter Open, Greater Current

Question 16

How does the NMJ form?

Answer 16

AChRs pre-aggregate in center of developing muscle fibers

AChRs become concentrate at region of interaction; increased by nerve

Existing receptors redistributed, new receptors made

Immature post-synaptic junctions present in developing muscle

Question 17

What proteins drives receptor clustering?

What releases it?

Answer 17

Agrin, released from the nerve

“Aggrin’gate”

Question 18

What protein does agrin activate?

What is its role?

Answer 18

Agrin activates Muscle-Specific Kinase (MuSK)

MuSK induces clustering by Rapsyn

“Rapsyn (wrapping) up the clusters for gifts”

The ‘K’ in MuSK is a kinase–it targets something for activation, it’s a middle-man

Question 19

What additional protein is required for Agrin to bind to MuSK?

What regulates this binding?

Answer 19

LRP4

Agrin regulates

Question 20

What additional protein is required for MuSK activation by the Agrin+LRP4 complex?

Answer 20

Dok-7

Question 21

What is the terrible mneumonic for the clustering of AChR’s?

Answer 21

Now, you’re ALMost DR CAstillo

Nerve

Agrin + LRP-4

MuSK + Dok-7

Rapsyn

Cluster AChRs

Question 22

What prevents clustering of receptors where they’re not needed? (e.g. negative signals)

Answer 22

ACh activates negative pathways

Question 23

When do the embryonic receptors disappear (in favor of adult)?

Answer 23

After innervation during development

Question 24

How many neurons are required per muscle fiber?

Answer 24

1 fiber = 1 nerve

Question 25

What occurs if muscle is denervated?

Answer 25

Them babies will grow back

Question 26

Botulinum Toxin

Answer 26

Blocks ACh Release

Question 27

What drugs affect AChRs?

Answer 27

Activate: Nicotine

Inhibit: d-tubocurarine (Curare), a-bungarotoxin (snake venome)

Question 28

What drugs affect AChE?

Answer 28

Inhibit:

Physostigmine

Neostigmine

Question 29

Tetrodotoxin

Answer 29

Blocks muscle Na+ channels

Question 30

Conotoxins

Answer 30

Block neuronal Ca²⁺ channels, muscle Na⁺ channels, and AChRs

Question 31

Myasthenia Gravis

Answer 31

Antibodies against AChRs

Antibodies to MuSK

Reduced AChR levels at NMJ, degeneration of postjunctional folds

Reduced EPPs and MEPPs

Safety factor gone, not enough receptors–exercise worsens

Question 32

What are treatments for Myasthenia Gravis?

Answer 32

AChE inhibitor; keep the neurotransmitter present at the synapse

Drugs to reduce immune response

Removal of AChR antibodies

Question 33

Clinical features of Myasthenia Gravis

Answer 33

Weakness and fatigue

Worsens by exercise

Eye strain = initial presentation

Question 34

Lambert-Eaton Syndrome

Answer 34

Make antibodies against presynaptic voltage-gated Ca²⁺ channels–reduced ACh release

Reduces neurotransmitter release, primarily limb muscles

Exercise can improve

Cancer can cause, as it attacks tumor Ca++ channels, and your muscle Ca++ channels also get hit

Question 35

Botulism

Answer 35

Inhibits synaptic vesicle release

Weakness, paralysis

Can be used to treat muscle spasms, cross-eyes, and headaches

Question 36

How does aging affect the NMJ?

Answer 36

Decreases over time, less likely to regenerate