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MSK > Pharmacology of the Neuromuscular Junction > Flashcards

Pharmacology of the Neuromuscular Junction Flashcards

1
Q

What are the steps involved in NMJ neurotransmission?

A
  1. axonal conduction
  2. junctional transmission (cholinergic)
    a) synthesis of acetylcholine (ACh)
    b) storage of ACh
    c) release of ACh
    d) destruction of ACh
  3. ACh signaling
  4. muscle contraction
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2
Q

What drug/toxin inhibits step 1 of junctional transmission, ACh synthesis?

What drug/toxin inhibits step 2 of junctional transmission, ACh storage?

What drug/toxin inhibits step 3 of junctional transmission, ACh release?

A
  • ACh synthesis: hemicholinium
  • ACh storage: vesamicol
  • ACh release: botulinium toxin
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3
Q

How is ACh synthesized?

A
  • choline transporter: membrane channel that transports choline into the cell
  • choline acetyltransferase (ChAT): enzyme that combines acetyl coenzyme A (AcCoA) and choline to form ACh

(there are pharmaceutical agents that inhibit ChAT, but they are of little use because the uptake of choline is the rate-limiting step in ACh biosynthesis)

*patients w/ Alzheimer’s dz have reduced cerebral production of ChAT

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4
Q

How is ACh stored in vesicles?

A
  • ACh vesicular transporter: ATP dependent transporter that immediately shuttles ACh into storage vesicles after ACh synthesis
  • 1K-50K molecules of ACh per vesicle
  • motor nerve terminal may contain over 300K vesicles
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5
Q

How is ACh released into the synaptic cleft?

A
  • voltage-gated Ca2+ channels: open upon depolarization and allow Ca2+ to enter the cell
  • Ca2+ promotes vesicle membrane fusion
  • VAMP and SNAPs: vesicular and plasma membrane proteins that initiate vesicle-plasma membrane fusion and release of ACh
  • roughly 125 vesicles rupture per AP
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6
Q

What is the molecular process of vesicle-membrane fusion in terms of ACh NT?

A
  1. vesicles w/ synaptotagmin (calcium sensor on vesicle membrane that triggers vesicle fusion and exocytosis) and synaptobrevin (aka VAMP), a v-SNARE, move to the nerve terminal membrane, which contains syntaxin and SNAP-25, both t-SNAREs
  2. n-sec 1 dissociates from syntaxin, allowing syntaxin and SNAP-25 to form a complex. The distal end of synaptobrevin begins to wind around the syntaxin/SNAP-25 complex, forming a ternary complex (SNARE complex)
  3. the 3 SNAREs continue to form a tight bundle of alpha-helices, drawing the vesicle and presynaptic membranes into close apposition
  4. entry of Ca2+ and its binding to synaptotagmin triggers fusion of vesicle and membrane
  5. alpha-SNAP and ATPase NSF bind to ternary SNARE complex and use the energy of ATP hydrolysis to disassemble the SNAREs
  6. w/ endocytosis of the vesicle, the synaptobrevin is effectively recycled. The syntaxin and SNAP-25 are now free for an additional cycle of vesicle fusion
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7
Q

How is ACh destroyed/recycled?

A
  • acetylcholinesterase (AChE): enzyme that cleaves ACh into choline and acetate
  • choline is recycled back into the motorneuron via the choline transporter
  • endocytosis occurs at the nerve terminal to replenish the number of available vesicles
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8
Q

How does ACh signaling occur via different receptors?

A
  • ACh activates two subsets of receptors: nicotinic (n) and muscarinic (m)

nAChRs:

a) activated by ACh and nicotine
b) ligand-gated ion channel
c) pre- and postjunctional
d) NMJ: Na+ increase causes muscle AP

mAChRs:

a) activated by ACh and muscarine
b) G-protein coupled receptor
c) pre- and postjunctional
d) NOT located on skeletal NMJ

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9
Q

nAChR:

  • tissue location:
  • function:
  • agonists:
A

nAChR:

  • tissue location: skeletal muscle
  • function: contraction
  • agonists: acetylcholine, nicotine
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10
Q

mAChR:

  • tissue location:
  • function:
  • agonists:
A

mAChR:

  • tissue location: smooth muscle
  • function: contraction
  • agonists: acetylcholine, muscarine

mAChR:

  • tissue location: cardiac muscle (SA node, AV node, atrium, ventricle)
  • function: decrease HR, conduction velocity, and contraction (slight)
  • agonists: acetylcholine, muscarine
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11
Q

What is the general mechanism of action of mAChRs?

A
  • mAChRs are GPCRs w/ 5 different substypes: M2 and M3 receptors predominate smooth muscle, M2 receptors predominate cardiac muscle
  • metabotropic receptors that do not form an ion channel pore
  • agonists binding activated intracellular G-proteins that trigger activation of intracellular signaling pathways
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12
Q

What is the general mechanism of action of nAChRs?

A
  • nAChRs are ligand-gated ion channels that allow ions to pass through the channel pore when activated (ionotropic)
  • fasted synaptic events in nervous system (miliseconds)
  • ions are selected based on the charge of amino acids lining pore of channel
  • negatively charged amino acids line pore of channels that pass positively charged ions and vice versa
  • nAChRs specifically: aspartic acid and glutamic acid line pore (negative charge) so channel can be selective to Na+, Ca2+, and K+
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13
Q

skeletal musle

  • main synaptic location:
  • membrane response:
  • molecular response:
  • agonists:
  • antagonists:
A

skeletal musle

  • main synaptic location: skeletal neuromuscular junction (postjunctional)
  • membrane response: excitatory, contraction
  • molecular response: increased cation permeability (Na+, K+)
  • agonists: ACh, nicotine, succinylcholine
  • antagonists: d-tubocurarine, Atracurium, Vecuronium, Pancuronium
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14
Q

peripheral neuronal

  • main synaptic location:
  • membrane response:
  • molecular response:
  • agonists:
  • antagonists:
A

peripheral neuronal

  • main synaptic location: autonomic ganglia; adrenal medulla
  • membrane response: excitatory, depolarization
  • molecular response: increased cation permeability (Na+, K+)
  • agonists: ACh, nicotine
  • antagonists: mecamylamine
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15
Q

central neuronal

  • main synaptic location:
  • membrane response:
  • molecular response:
  • agonists:
  • antagonists:
A

central neuronal

  • main synaptic location: CNS
  • membrane response: excitatory, pre-junctional control of ACh release
  • molecular response: increased cation permeability (Na+, K+, Ca2+)
  • agonists: ACh, nicotine
  • antagonists: mecamylamine
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16
Q

What is the complete process of transmitting ACh across a NMJ?

A
  1. an AP in the motor neuron is propagated to the terminal buttom
  2. presence of an AP triggers the opening of voltage-gated Ca2+ channels
  3. Ca2+ triggers the release of ACh from vesicles
  4. ACh diffuses across the synaptic cleft and activates nAChRs
  5. nAChRs open leading to a relatively large influx of Na+ compared to a smaller efflux of K+
  6. local current flows between the depolarized end plate and adjacent membrane
  7. local flow opens voltage-gated Na+ channels
  8. influex of Na+ initiates an AP, which propagates throughout the muscular fiber
  9. ACh is destroyed by AChE, terminating the muscle cell’s response
17
Q

Agents that affect nerve action potential:

A
  • Tetrodotoxin
  • local anesthetics
18
Q

Agents that affect vesicular acetylcholine release:

A
  • Botulinum toxin
  • Tetanus toxin
19
Q

Agents that affect depolarization:

A

(neuromuscular blocking drugs)

  • Curare alkoids (d-tubocurarine)
  • succinylcholine
20
Q

Agents that inhibit acetylcholinesterase:

A
  • acetylcholinesterase inhibitors
21
Q

Agents that affect muscle action potential:

A
  • Tetrodotoxin
22
Q

Agents that affect muscle contraction:

A
  • Dantrolene

(figure is a study tool and summary of agents that act on NMJ)

23
Q
  • puffer fish poison (fugu, globefish, blowfish); not used clinically
  • MOA: inhibition of voltage-gated Na+ channels blocks axonal conduction
  • sx: weakness, dizziness, paresthesias of face/extremities, loss of reflexes, hypotension, generalized paralysis, death can occur due to respiratory failure and hypotension
A

Tetrodotoxin

(affects nerve action potential and muscle action potential)

24
Q
  • MOA: inhibition of voltage-gated Na+ channels inhibit axonal conduction
  • utilized for pain control during a variety of clinical procedures
  • ex: Lidocaine, Bupivacaine, Procaine
A

local anesthetics

(affects nerve AP, Procaine also affects vesicular ACh release)

25
Q
  • toxin released by Clostridium botulinum, a heterogenous group of gram-positive, rod-shaped, spore-forming, obligate anaerobic bacteria; found on vegetables, fruits, seafood; exists in soil and marine sediment worldwide
  • MOA: cleaves components of the core SNARE complex involved in exocytosis, preventing release of ACh
  • sx: acute onset of bilateral cranial neuropathies a/w symmetric descending weakness, no sensory deficits w/ exception of blurred vision
  • foodborn sx: nausea, vomiting, abd pain, diarrhea, dry mouth
  • clinical uses: temporary improvement of appearance of lines/wrinkles on face, prophylaxis of chronic migraine headaches
A

botulinum toxin

(affects vesicular ACh release)

26
Q
  • nervous system disorder characterized by muscle spasms that are caused by toxin-producing anaerobe, Clostridium tetani, which is found in soil
  • MOA: block fusion of synaptic vesicles by targeting synaptobrevin; after binding to presynaptic membrane of NMJ this toxin is internalized and transported retroaxonally to the spinal cord; spastic paralysis is caused by toxin’s actions on the spinal inhibitory interneurons, blocking release of inhibitory NT’s that normally serve to relax contracts muscle by inhibiting excitatory motor neurons
  • sx: spastic paralysis, trismus (lockjaw), autonomic overactivity (restlessness, sweating, tachycardia), stiff neck, board-like rigid abdomen, opisthotonus, dysphagia
A

Tetanus toxin

(affects vesicular ACh release)

27
Q
  • neuromuscular blocking drug
  • MOA: competes w/ ACh for the nAChR on the motor end plate, decreasing the size of the EPP (nondepolarizing competitive nAChR antagonist)
  • inhibition of ACh binding to nAChR leads to flaccid paralysis of skeletal muscle
  • used during anesthesia to relax skeletal muscle
  • paralysis reversed by increasing ACh in NMJ (AChE inhibitor)
A

Curare alkaloids (d-tubocurarine)

(affect depolarization, neuromuscular blocking agent)

28
Q
  • neuromuscular blocking drug
  • MOA: depolarizing neuromuscular blocker that binds to skeletal muscle nAChRs and initially causes depolarization (acts as an agonist; muscle fasiculations); continued depolarization leads to receptor blockade and paralysis
  • used as induction agent for anesthesia
  • paralysis reversed by termination of effects (i.e. time)
A

succinylcholine

(affects depolarization, neuromuscular blocking agent)

29
Q
  • bind to AChE and block its enzymatic activity
  • increase the conc of ACh at the NMJ
  • clinical uses: dementia a/w Alzheimer or Parkinson dz, myasthenia gravis, nerve gas and organophosphate pesticide exposure, and reversal of neuromuscular blockade during anesthesia
A

cholinesterase inhibitors

(inhibits AChE)

30
Q
  • inhibits ryanodine receptors in the sarcoplasmic reticulum and blocks release of Ca2+
  • clinical uses: malignant hyperthermia, spasticity a/w upper motor neuron disorders
A

Dantrolene

(agent that affects muscle contraction)

MSK (33 decks)

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