Pharmacology - NMJ

Question 1

Steps involved in NMJ neurotransmission

Answer 1

1. Axonal conduction
2. Junctions transmission
3. ACH signaling
4. Muscle contraction

Question 2

Junctions transmission

Answer 2

1. ACH synthesis
2. ACH storage
3. ACH release
4. ACH destruction

Question 3

Membrane channel that transports choline into cell

Answer 3

Choline transporter

Question 4

Enzyme that combine acetyl coenzyme A (AcCoA) and choline to form ACH

Answer 4

Choline acetyltransferase (ChAT)

Question 5

Choline transporter inhibitor

Answer 5

Hemicholinium

Question 6

Opens upon depolarization and allows Ca2+ to enter the cell

Answer 6

Voltage-gated Ca2+ channels

Question 7

What does release of Ca2+ via voltage-gated Ca2+ channels promote?

Answer 7

Vesicle membrane fusion

Question 8

Vesicular and plasma membrane proteins that initiate vesicle-plasma membrane fusion and release of ACh

Answer 8

VAMP and SNAPs

Question 9

What does acetylcholinesterase (AChE) cleave acetylcholine into?

Answer 9

Choline and acetate

Question 10

What happens to the choline produced by breakdown of ACh?

Answer 10

Recycled back into motor neuron via choline transporter

Question 11

What process occurs are the nerve terminal to replenish number of available vesicles?

Answer 11

Endocytosis

Question 12

2 subsets of acetylcholine receptors

Answer 12

• nicotonic acetylcholine receptors (nAChRs)

- muscarinic (mChRs)

Question 13

• activated by ACh and nicotine
• ligand-gated ion channel (Na+)
• pre and post-junctions
• at NMJ: Na+ increase causes muscle AP

Answer 13

NAChRs

Question 14

• activated by ACh and muscadine
• GPCR
• pre and post-junctions
• NOT located at skeletal NMJ

Answer 14

MAChR

Question 15

Where are mAChRs found?

Answer 15

• smooth muscle

- cardiac muscle

Question 16

Function of nAChR and mAChr in skeletal muscle and smooth muscle (respectively)

Answer 16

Contraction

Question 17

Function of mAChR in cardiac muscle

Answer 17

Decreased HR, conduction velocity, contraction

Question 18

Number of mAChR subtypes in mammals

Answer 18

5 (M1-M5)

Question 19

Metabotropic

Answer 19

Activation leads to series of intracellular events triggered by second messengers

Question 20

Ionotropic

Answer 20

Ligand-gated ion channels allow ions to pass through channel pore when activated

Question 21

Describe selectivity of ions

Answer 21

Based on charge of amino acid

Ex: negative charge within pore of nAChR = allows positive ions to pass

Question 22

Molecular response of all types of nAChRs

Answer 22

Increased cation permeability (Na+ and K+; Ca2+ in CNS)

Question 23

Agonists of skeletal muscle (Nm)

Answer 23

ACh
Nicotine
Succinylcholine

Question 24

Antagonists of skeletal muscle (Nm)

Answer 24

• d-tubocurarine
• atracurium
• vecuronium
• pancuronium

Question 25

Antagonists of peripheral neuronal (Na) and central neuronal receptors

Answer 25

Mecamylamine

Question 26

Synaptic location for peripheral neuronal (Nn) vs. central neuronal

Answer 26

- peripheral neuronal: autonomic ganglia & adrenal medulla - central neuronal: CNS

Question 27

Events at the NMJ

Answer 27

1. AP propagated to terminal button 2. AP triggers opening of voltage-gated Ca2+ channels 3. Ca2+ triggers release of ACh from vesicles 4. ACh diffuses across synaptic cleft and activates nAChRs 5. NAChRs open > large include of Na+ compared to small effluent K+ 6. Local current flows b/w de polarized end plate and adjacent membrane 7. Local flow opens voltage-gated Na+ channels 8. Influx of Na+ initiates an AP which propagates throughout muscle fiber 9. ACh is destroyed by ACHE, terminated cells response

Question 28

Tetrodotoxin, batrachotoxin, local anesthetics

Answer 28

Block nerve AP

Question 29

Hemicholinium, botulinum toxin, procaine, Mg2+, 4-aminopyridine, lack of Ca2+

Answer 29

Block vesicular acetylcholine release

Question 30

Excess of Ca2+

Answer 30

Promotes vesicular acetylcholine release

Question 31

Curare alkaloids and snake alpha-toxins

Answer 31

Block depolarization (EPP) (increased permeability to Na+ and K+)

Question 32

Succinylcholine and decamethonium

Answer 32

Depolarization and phase II block

Question 33

Cholinesterase inhibitors

Answer 33

Block hydrolysis of acetylcholine by cholinesterase

Question 34

Ca2+ and veratridine

Answer 34

Enhance muscle AP

Question 35

Quinine and tetrodotoxin

Answer 35

Block muscle AP

Question 36

Metabolic poisons, lack of Ca2+, procaine, dantrolene

Answer 36

Block muscle contraction

Question 37

- puffer fish poison - inhibition of voltage-gated Na+ channels block axonal conduction - weakness, dizziness, paresthesia of face and extremities, loss of reflexes, hypotension, general paralysis, death from respiratory failure and hypotension

Answer 37

Tetrodotoxin

Question 38

- inhibition of voltage-gated Na+ channels inhibition axonal conduction - used for pain control during clinical procedures - ex: lidocaine, bupivicaine, procaine

Answer 38

Local anesthetics

Question 39

- cleaves components of core SNARE complex involved in exocytosis, preventing release of ACh - caused by Clostridium botulinum (heterogenous group of gram-positive, rod-shaped, sport-forming, obligate anaerobic bacteria; found on vegetabless, fruits, seafood, etc.) - classically described as cute onset of bilateral cranial neuropathies associated with symmetric descending weakness - used with temporary improvement in appearance of lines/wrinkles of face, prophylaxis of chronic migraine headache

Answer 39

Botulinum toxin

Question 40

Nervous system disorder characterized by muscle spasms caused by Clostridium tetani (toxin-producing anaerobes) found in soil

Answer 40

Tetanus

Question 41

- block fusion of synaptic vesicles by targeting synaptobrevin - after blinding to presynaptic membrane of NMJ, tetanus toxin is internalized and transported retroaxonally to SC - spastic paralysis caused by toxins actions on spinal inhibitory interneurons, blocking release of inhibitory NT that serve to relax contracted muscle by inhibiting excitatory motor neurons

Answer 41

Tetanus toxin

Question 42

Spastic paralysis with symptoms that include trismus, autonomic overactivity, stiff neck, board-like rigid abdomen, opisthotonos, dysphasia

Answer 42

Symptoms of tetanus

Question 43

Activate receptor to signal as a direct result of binding to it

Answer 43

Agonist

Question 44

Bind to receptors but do not activate generation of signal

Answer 44

Antagonists

Question 45

- Competes with ACh for the nAChR on the motor end plate > decrease size of EPP - inhibits ACh binding to nAChR > flaccid paralysis of skeletal muscle - used during anesthesia to relax skeletal muscle - paralysis reversed by increasing ACh in the NMJ

Answer 45

Curare alkaloids (d-tubocurarine)

Question 46

- depolarizing neuromuscular blocker that binds to skeletal muscle nAChRs and causes depolarization > continued depolarization leads to receptor blockade and paralysis - used as induction agent for anesthesia - paralysis reversed by termination of succinylcholine’s effects

Answer 46

Succinylcholine

Question 47

- bind to AChE and block enzymatic activity - increase concentration of ACh at the NMJ - clinical uses: dementia (Alzheimer’s or Parkinson’s), myasthenia Travis, nerve gas and organophosphate pesticide exposure, reversal of neuromuscular blockade during anesthesia

Answer 47

Cholinesterase inhibitors

Question 48

- inhibit RyR in the SR and blocks release of Ca2+ | - clinical use: malignant hyperthermia, spasticity associated with upper motor neuron disorders

Answer 48

Dantrolene

Question 49

blocks the ACh vesicular transporter

Answer 49

Vesamicol