Pharmacology of Neuromuscular Junction

Question 1

Primary NT for skeletal muscle is

Answer 1

Ach

Question 2

Choline acetyltransferase

Answer 2

Combines acetyl CoA and choline to form ACh

Patients with alzheimers disease have reduced cerebral production of ChAT

Question 3

ACh release

Answer 3

Voltage gated Ca2+ channels open upon depolarization
Ca2+ promotes vesicle membrane fusion
VAMP and SNAPs- proteins that initiate fusion and release of ACh

Question 4

Nicotinic ach receptors

Answer 4

Ligand gated ion channels
Pre and post junctional
NMJ: Na+ increase causes muscle action potential

Question 5

Muscarinic ach receptors

Answer 5

Activated by Ach and muscarine
G-protein coupled receptor
Pre and post junctional
Not found at skeletal NMJ- only smooth muscle

Question 6

Effects of activation of mAChR in cardiac muscle

Answer 6

Act at SA/AV nodes, atrium and ventricles

Decrease heart-rate, conduction velocity and contraction

Question 7

Antagonists of skeletal muscle nAChRs

Answer 7

d-tubocurarine
Atracurium
Vecuronium
Pancuronium

Question 8

Agonists of skeletal muscle nAChRs

Answer 8

ACh, nicotine, succinylcholine

Question 9

Antagonists of peripheral/central neuronal nAChRs

Answer 9

Mecamylamine

Question 10

Events at the NMJ with nAChRs

Answer 10

AP in motor neuron is propagated to the terminal button
Triggers opening of VGCC
Ca triggers release of ACh
nAChRs across synaptic cleft are activated
nAChRs open leading to a large influx of Na and small influx of K
Current flows between depolarized end plate and adjacent membrane
Local flow opens VG Na channels
AP is triggered, propagating through muscle fiber
ACh destroyed

Question 11

Tetrodotoxin

Answer 11

Inhibits VG Na channels
Generalized paralysis
Loss of reflexes
Paresthesia of face/extremities
Weakness, dizziness, hypotension
Death

Question 12

Local anesthetics lidocaine or other caines

Answer 12

Inhibit voltage gated Na channels

Question 13

Botulinum toxin

Answer 13

Cleaves component of core SNARE complex involved in exocytosis, preventing release of ACh

Question 14

Tetanus toxin

Answer 14

Blocks fusion of synaptic vesicles by targeting synaptobrevin
Spastic paralysis results because tetanus is transported to the spinal cord and blocks the spinal inhibitory neurons which would usually serve to relax contracted muscle
-Trismus (lockjaw), autonomic overactivity, stiff neck, dysphagia

Question 15

Curare alkaloids- d-tubocararine

Answer 15

Competes with ACh for binding to receptor
Inhibits receptor causing flaccid paralysis of skeletal muscle
Used during anesthesia to relax muscle
Reversed by increasing ACh

Question 16

Succinylcholine

Answer 16

Binds to nAChRs and initially causes depolarization; continued depolarization leads to receptor blockade and paralysis
Used as induction agent for anesthesia

Question 17

Cholinesterase inhibitor clinical uses

Answer 17

Dementia associated with Alzheimer or parkinsons disease
Myasthenia gravis
Nerve gas/organophosphate pesticide exposure
Reversal of NMJ blockade during anesthesia

Question 18

Dantrolene

Answer 18

Inhibits ryanodine receptors in the sarcoplasmic reticulum and blocks release of Ca
Used in malignant hyperthermia, spasticity associated with upper motor neuron disorders

Question 19

Synaptobrevin

Answer 19

Vesicle associated membrane protein VAMP

Question 20

Syntaxin

Answer 20

Target associated membrane protein SNAP-25

Question 21

Synaptotagmin

Answer 21

Calcium sensor protein located on vesicular membrane