PHARM Lecture

Question 1

How many NMJ per myofiber?

Answer 1

1

Question 2

What are the steps involved in NMJ transmission?

Answer 2

1)Axonal conduction
●
2)Junctional transmission (cholinergic)
1)Synthesis of acetylcholine (ACh)
2)Storage of ACh
3)Release of ACh
4)Destruction of ACh
●
3)ACh signaling
●
4)Muscle contraction

Question 3

Describe step 1

Answer 3

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

Question 4

Patients with Alzheimer Disease (AD) have reduced cerebral production of what?

Answer 4

ChAT

Question 5

Describe step 2

Answer 5

ACh vesicular transporter: ATP dependent transporter that immediately shuttles ACh into storage vesicles after ACh synthesis

Question 6

Describe step 3

Answer 6

• 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

Question 7

What are the two main classes of snares?

Answer 7

V snares and T snares

Question 8

Botulinum toxin has what effect?

Answer 8

Cleave V or T snares, and prevents release of Ach

Question 9

Describe VAMPs

Answer 9

•vesicle associated membrane protein (v-SNARE)

Question 10

Describe SNAPs

Answer 10

•synaptosome-associated proteins (t-SNARE)

Question 11

Describe step 4

Answer 11

•Acetylcholinesterase (AChE): enzyme that cleaves ACh into choline and acetate
•
•Choline is recycled back into the motor neuron via the choline transporter
•
•Endocytosis occurs at the nerve terminal to replenish the number of available vesicles

Question 12

What are the two subsets of receptor that ACh signaling utilize?

Answer 12

Nicotinic and muscarinic

Question 13

Describe the nicotinic subtype of receptor

Answer 13

• nAChRs
• Activated by ACh and nicotine
• Ligand-gated ion channel (Na+)
• Pre- and postjunctional
• NMJ: Na+ increase causes muscle action potential

Question 14

What subtype of ACh receptor is at the NMJ?

Answer 14

Nicotinic Receptor

Question 15

Nicotinic receptors are what kind of receptor?

Answer 15

Ionotropic

Question 16

Describe muscarinic receptors

Answer 16

• mAChRs
• Activated by ACh and muscarine
• G-protein coupled receptor
• Pre- and postjunctional
• NOT located at skeletal NMJ

Question 17

Both nicotinic and muscarinic receptors can be found…

Answer 17

either post or pre synaptically

Question 18

What agonists work on nAChR?

Answer 18

Acetylcholine

Nicotine

Question 19

Where are mAChR found?

Answer 19

Cardiac muscle

• SA Node
• AV Node•Atrium
• Ventricles

Question 20

What kind of receptor is pictured?

Answer 20

Nicotinic

Question 21

What is important about nAChR subunit composition?

Answer 21

Diversity in subunit composition permits drug selectivity. Neuronal and muscle subunit configuration are different.

Question 22

Describe post junctional nAChR activation

Answer 22

• ACh binds at two sites on the NM receptor
• A conformational change opens the channel pore
• Positively charged ions (mostly Na+, but also K+ and Ca2+) pass through the channel
• The muscle cell is depolarized and an action potential is initiated

Question 23

describe pre-junctional nAChr activation

Answer 23

•Mobilization of additional ACh for subsequent release
•ACh vesicles move toward the synaptic membrane
•
•
•mAChR activation results in ACh-mediated inhibition of further ACh release

Question 24

Key concept about these receptors…

Found on…

Actions dependent upon…

Answer 24

… before and after the synapse

… on the subunit conformation

Question 25

Describe tetrodotoxin

Answer 25

•(puffer fish): similar mechanism as local anesthetics (different binding site on Na+ channels)

Paralysis, including the diaphragm, leading to suffocation

Question 26

How do local anesthetics function?

Answer 26

•inhibition of voltage-gated Na+ channels prevents axonal conduction

Question 27

Describe Botulinum Toxin (Botox):

Answer 27

•cleaves components of the SNARE complex (VAMP/SNAP proteins)

Question 28

What are two agents that block muscle depolarization?

What are they used for?

Answer 28

Curare alkaloids

succinylcholine

•Used for causing muscle paralysis during anesthesia

Question 29

What do curare alkaloids do?

Answer 29

nondepolarizing competitive nAChR antagonists

Question 30

Succinylcholine does what?

Answer 30

•depolarizing neuromuscular blocker that binds to skeletal muscle nAChRs and initially causes depolarization (acts as an agonist); continued depolarization leads to receptor blockade and paralysis
(Can’t initiate a new depolarization or muscle contraction)

Question 31

What drugs are represented by the green and red shapes?

Answer 31

Green - Curare Alkaloids

Red - Succinylcholine

Question 32

What are the clinical uses of Acetylcholinesterase inhibitors

Answer 32

• Myasthenia gravis **** Highly useful
• Dementia associated with Alzheimer or Parkinson disease
• Reversal of neuromuscular blockade during anesthesia
• Nerve gas and organophosphate pesticide exposure

Question 33

How do AChE inhibitors work?

Answer 33

• Bind to AChE and block its enzymatic activity
• Increase the concentration of ACh at the NMJ

Question 34

What is Sarin gas an example of?

How can you prevent death due to this?

Answer 34

AChE inhibitor, extremely high concentration and long acting.

Atropene, or a short acting AChE inhibitor to bind the AChE first, preventing binding of the warfare agent.

Question 35

Describe dantrolene’s action

Answer 35

•Inhibits ryanodine receptors in the sarcoplamic reticulum and blocks release of Ca2+

Question 36

What clinical uses are there for Dantrolene?

Answer 36

•nical uses include malignant hyperthermia and spasticity associated with upper motor neuron disorders