Pharmacology of the Neuromuscular Junction

Question 1

ACh Synthesis: choline transporter

Answer 1

Membrane channel that transports the choline into the cell

Question 2

ACh Synthesis: Choline acetyltransferase and impact on patients with alzheimers

Answer 2

Enzyme that combine acetyly Coenzyme A and choline to form ACh

Patients that have Alzheimers disease have reduced Cerebral production of ChAT (choline acetyltransferase

Question 3

ACh Storage: ACh vesicular transporter

Answer 3

ATP dependant transporter that shuttles ACh into the storage vesicles after the production of ACh

a motor nerve terminal may contain 300k of these

Question 4

ACh Release: Voltage gated Ca2+ channels

Answer 4

these open upon depolarization of the cell that allow the Ca2+ to enter the cell and promote vesicle membrane fusion

Question 5

ACh Release: VAMP and SNAP

Answer 5

vesicular and plasma membrane proteins that initiate vesicle plasma membrane fusion and release of the ACh

about 125 of these vesicles rupture per action potential

Question 6

ACh Destruction: Acetylcholinesterase (AChE)

Answer 6

enzyme that cleaves the ACh into choline and acetate

choline will then recycle back to the motorneuron via the choline transporter

Question 7

Nicotinic Acetylcholine receptors:

Answer 7

activated by ACh and nicotine
ligand gated ion channel (Na+)
Pre- and post junctional
NMJ: Na+ increases causes muscle action potential

Found at Skeletal muscle

ionotropic- ligand gated ion channels that allow for ions to pass through the channel pore when activated

Question 8

Muscarinic Acetycholine receptors

Answer 8

Activiated by ACh and muscarine
G protein coupled receptor
Pre and post junctional
Not located at skeletal NMJ

at smooth muscle and cardiac muscle

decreases HR and contraction

metabotropic- activation leads to intracellular events that trigger secondary messengers

Question 9

How are the Ligand Gated Ion channels selective?

Answer 9

Ions are selected based on the charge of the amion acids lining the pore of the channel

Negative charged amino acids line the pore of channels that pass positively charged ions

Positive charged amino acids line the pore of channels that pass negatively charged ions through it

Question 10

what line the LGIC in nAChRs

Answer 10

Aspartic acid and glutamic acid line pore (negative charge)

allow for the channel to be selective to Na+, Ca2+, and K+

Question 11

nAChRs Skeletal muscle receptor Nm characteristics: Synaptic location, membrane response, Molecular response

Answer 11

location: Skeletal Neuromuscular junction

Membrane response: Excitatory, contraction

Molecular response: Increased cation permeability (Na+, K+)

Question 12

nAChRs Skeletal muscle receptor (Nm) characteristics: Agonists, and antagonists

Answer 12

Agonists: ACh, Nicotine, succinylcholine

Antagonists: d-tubocurarine
Atracurium
Vecuronium
Pancuronium

Question 13

nAChRs Peripheral Neuron receptor (Nn) Characteristics: Synaptic location, membrane response, Molecular response

Answer 13

Synaptic location: Autonomic ganglia, adrenal medulla

Membrane response: Excitatory, depolarization

Molecular response: Increased permeabillity (Na+, K+)

Question 14

nAChRs Peripheral Neuron receptor (Nn) characteristics: Agonists, Antagonists

Answer 14

Agonists: ACh, Nicotine

Antagonists: Mecamylamine

Question 15

nAChRs Central Neuron receptor Characteristics: Agonists, antagonists

Answer 15

Agonists:ACh, and Nicotine

Antagonists: Mecamylamine

Question 16

nAChRs Central Neuron characteristics: Synaptic location, membrane response, Molecular response

Answer 16

Synaptic Location: CNS

Membrane response: Excitatory pre-junctional control of ACh release

Molecular response: Increased cation permeabillity (Na+, K+, and Ca2+)

Question 17

9 Events that occur at the NMJ

Answer 17

1) an Action potential in the motor neuron is propagated to the terminal button
2) THe presence of an AP triggers the opening of the voltage-gated Ca2+ channels
3) Ca2+ triggers the release of ACh from vesicles
4) ACh diffuses across the synaptic cleft and activates the 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 current flow opens voltage gated Na+ channels
8) Influx of Na+ initiates an AP, which propagates throughout the muscle fiber
9) ACh is destroyed by the AChE terminating the muscles cells response

Question 18

Tetrodoxin

Answer 18

Affects Nerve AP

Puffer fish poison, not used clinically,

inhibition of voltage gated Na+ channels blocks axonal conduction

Symptoms: weakness, dizziness, paresthesias of face and exftremities, loss of reflexes, hypotension, generalized paralysis, death can occur due to respiratory failure and hypotension

Question 19

Local Anesthetics:

Answer 19

Affects Nerve AP

Inhibition of voltage gated Na+ channels inhibition axonal conduction

utilized for pain control during a variety of clinical procedures

Lidocane, bupivacaine, procaine

Question 20

Botulinum Toxin

Answer 20

Affects Vesicular Release

Botulism caused by clostridium botulinum, gram positive spore forming anerobic bacteria
found on vegetables, fruits, seafood, and exists in soil and marine sediment

MOA: cleaves components of the core SNARE complex involved in exocytosis preventing the release of ACh

classically described as acute onset of bilateral craniel neuropathises leading to symmetric descending weakness

blurred vision,
foodborne lead to nausea, vomiting, abdominal pain, diarrhea, and dry mouth

used for appearance and chronic migraine headache

Question 21

Tetanus Toxin

Answer 21

Affects the vesicular ACh release

Nervous system disorder characterized by muscle spasms that are caused by the toxin producing anaerobe Clostridium Tetani which is found in the soil

MOA: Blocks fusion of the synaptic vesicles by targeting synaptobrevin

the toxin binds to the presynaptic membrane and then is internalized and transported to the spinal cord

it then acts on the spinal inhibitory interneurons blocking the release of inhibitory neurotransmitters that normally serve to relax contracted muscles

spastic paralysis with things like lockjaw
autonomic overactivity, (restlessness, sweating, tachycardia) stiff neck, board like abdomen

Question 22

How do agonists and antagonists of the nAChR prevent synaptic transmission

Answer 22

Agonists: activate the receptor to signal as a direct result of binding it

antagonists: bind to receptors but do not activate generation of a signal

Question 23

Curare Alkolids

Answer 23

Affects Depolarization

d-tubocurarine is the prototype

Competes with the ACh for the nAChR on the motor end plate, it decreases the size of the EPP (nondepolarizing competitive nAChR antagonists

leads to flaccid paralysis of the skeletal muscle

makes the skeletal muscle relax

can be reversed by increasing the ACh in the NMJ (AChE inhibitor)

Question 24

Succinylcholine

Answer 24

Affects depolarization

Depolarizing neuromuscular blocker that binds to skeletal muscle nAChRs and initially causes a depolarization (acts as an agonist), but then continued depolarization leads to receptor blockade and paralysis

used as an induction agent for anesthesia

paralysis reversed by termination of succinylcholines effects

Question 25

Cholinesterase Inhibitor

Answer 25

Inhibits AChE

bind to AChE and vlocks its enzymatic activity

increases the concentration of ACh at the NMJ

used for demential associated with alzheimers or Parkinson, myasthenia gravis, nerve gasm and organophosphate pesticide exposure, reversal of neuromuscular blockade during anesthesia

Question 26

Dantrolene

Answer 26

Affects muscle contraction

inhibits the ryanodine receptors in the sarcoplasmic reticulum and blocks the release of Ca2+

used for malignant hyperthemia, spasticity associated with upper motor neuron disorders