Pharmacology of the Neuromuscular Junction

Question 1

What are the four steps in NMJ neurotrasmission?

Answer 1

1) axonal conduction
2) Junctional Transmission (4 steps)
3) ACh signaling
4) Muscle contraction

Question 2

What are the four steps in junctional transmission?

Answer 2

1. ACh synthesis (NT)
2. ACh storage
3. ACh release
4. ACh destruction

Question 3

What are the two main steps in ACh (acetylcholine) synthesis?

Answer 3

1. Choline is transported into the cell by a choline transporter
2. Choline acetyltransferase (ChAT) combines acetyl coenzyme A (AcCoA) and choline to form ACh

Question 4

How is ACh stored in a pre synaptic neuron and how many are in each synaptic vessle?

Answer 4

Once ACh is made, it is transporter into the storage vessicle by using ATP dependent ACh vesicular transporter. Approx. 1K-50K ACh per vessicle

(motor nerve terminals contain 300K)

Question 5

What are the main factors to the release of ACh? (2)

Answer 5

1. voltage gated Ca2+ channels open upon depolarization and Ca enters, promoting vesicle membrane fusion
2. VAMPS/SNAPS (vesicular plasma membrane proteins) initiate vesicle-plasma membrane fusion and release of ACh (125 vesicles per AP)

Question 6

What are the main steps in ACh destruction after it elicits a post synaptic response?

Answer 6

Acetylcholinesterase (AChE) will cleave ACh into choline and acetate.
Choline is reuptaked into cells via choline transporter

Question 7

What is unique to nAChRs to which ACh can bind? (4)

Answer 7

Activated by ACh/Nicotine, ligand gated ion channel (Na+), pre and post junctional, NML: Na+ increase causes AP

Question 8

What is unique to mAChRs to which Ach can bind? (4)

Answer 8

activated by ACh/Muscarine, GPCR, Pre/postjunctional, not located at skeletal NMJ

Question 9

What receptor for ACh when activated leads to a series of intracellular events triggered by secondary messengers (metabotropic), whose cellular effects are measured in seconds?

Answer 9

mAChRs

Question 10

What receptor for ACh actives ligand gated ion channels which allow ions to pass through the channel pore when activated (ionotropic), whose cellular effects are measured in miliseconds?

Answer 10

nAChRs

Question 11

The ions that go through a ligand gated ion are selected based on the charge of the amino acids lining the channel, what amino acids line the nAchRs and what do they have selectivity to?

Answer 11

Aspartic acid and glutamic acid line the pore (negative charges) meaning it needs positive charged molecules such as Na+, Ca+ and K+ to go through (more Na+ in skeletal muscle)

Question 12

Tertrodotoxin (What is it, MOA, Symptoms)?

Answer 12

Puffer fish poison

Inhibits voltage-gated Na+ channels, blocks axonal conduction (affects AP)

Weakness, Dizziness, Parethesias of face/extremities

Question 13

Local anesthetics (MOA, derivatives)?

Answer 13

Inhibits voltage gated Na+ channels, blocking axonal conduction (affects AP)

Used for pain control: lidocaine, bupivacaine, procaine

Question 14

Botulinum Toxin (What is it, MOA, Symptoms)?

Answer 14

gram-pos, rod shaped anaerobic bacteria in fruits/vegs/soil

cleaves core SNARE complex involved in exocytosis, preventing release of ACh from vesicle

clinically used for lines and wrinkles of the face/ prophylaxis of chronic migraine headache

Question 15

Tetanus Toxin (What is it, MOA, Symptoms)?

Answer 15

Nervous system disorder characterized by muscle spasms, caused by toxin producing clostridium tetani in soil

blocks flusion of synaptic vesicles/release of ACh by targeting synaptobrevin, once binds to NMJ will go to spinal cord and inhibit release of inhibitory neurotramsitters that normally serve to relax contracted muscle by inhibiting excitatory motor neurons

Spastic paralysis, jawlock, restlesness/sweating, stiff neck, rigid abdomen, dysphagia

Question 16

Agonist vs. antagonist in neuromuscular blocking of nAChRs?

Answer 16

Agonist: activate receptor to signal d/t binding to it
Antagonist: binds to receptor but do not activate signal

Question 17

Curare alkaloids-Antagonist (What is it, MOA, Symptoms)?

Answer 17

d-tubocurarine (nondepolarizing blocker)

competes with ACh for the nAChR on motor end plate, decreasing size of EPP - inhibition of ACh binding to the nAChR (no depolarization!) leads to flaccid paralysis of muscles

used in anesthesia to relax muscle, reversed by increasing ACh in the NMJ - AChE inhibitor

Question 18

Succinylcholine- agonist (What is it, MOA, Symptoms)?

Answer 18

depolarizing nueromuscular blocker that binds to skeletal muscle nAChRs and initially cause depolarization, and continued depolarization leads to receptor blockade and paralysis because does not close

used as induction agent for anesthesia, paralysis reversed by time (metabolism metabolizes it)

Question 19

Cholinesterase inhibitors (What is it, MOA, Symptoms)?

Answer 19

Bind to AChE and block enzymatic activity, increasing the concenctration of ACh at the NMJ

Used for dementia associated with alzheimer/parkinson, myasthenia gravis, nerve gas

Question 20

Dantrolene (What is it, MOA, Symptoms)?

Answer 20

Inhibits ryanodine receptors (end feet) in sarcoplasmic reticulu, and blocks release of Ca2+ (blocking muscle contraction)

Used in malignant hyperthermia, spasticity associated with upper motor neuron disorders

Question 21

Agents that affect the nerve action potential? (2)

Answer 21

Tetrodotoxin

Local Anesthetics

Question 22

Agens that affect vesicular acetylcholine release? (2)

Answer 22

Botulinum toxin

Tetanus toxin

Question 23

Agents that affect depolarization? (2) (Neuromuscular blocking drugs)

Answer 23

Curare alkaloids (d-tubocurarine)
Succinylcholine

Question 24

Agent that inhibit acetylcholinesterase?

Answer 24

Acetylcholinesterase inhibitors

Question 25

Agent that affect the muscle action potential?

Answer 25

Tetrodotoxin

Question 26

Agent that affect muscle contraction (block ryanodine the end feet between t tubules SR)?

Answer 26

Dantrolene