Cholinergic Pharmacology at the NMJ

Question 1

When an action potential travels down a neuron to depolarise the synaptic bouton, the influx of proteins causes vesicles containing NT to move to the pre-synaptic membrane, how does this occur?

Answer 1

Ca2+ causes the contraction of pre-synaptic grid proteins, this draws the vesicles forward towards the membrane where they fuse

Question 2

Which kind of receptors does Ach bind to?

Answer 2

Either nicotinic or muscarinic receptors Nicotinic receptors are found at the NMJ

Question 3

How is Ach made?

Answer 3

Choline within the nerve terminal is acetylated by choline acetyl transferase (CAT)

Question 4

When an action potential invades the terminal, ______ triggers Ca++ influx which leads to vesicle _______, fusion and ______, ie. the vesicular membrane fuses with the terminal membrane and expels acetylcholine molecules and co-transmitter molecules into the synaptic cleft

Answer 4

When an action potential invades the terminal, depolarisation triggers Ca++ influx which leads to vesicle mobilisation, fusion and exocytosis, ie. the vesicular membrane fuses with the terminal membrane and expels acetylcholine molecules and co-transmitter molecules into the synaptic cleft

Question 5

What breaks down acetylcholine in the synaptic cleft?

Answer 5

Acetylcholinesterase breaks down Ach into choline and acetate

Question 6

What do Acetylcholinesterase inhibitors do?

Answer 6

They inhibit the enzyme acetylcholinesterase, enhancing cholinergic transmission

Question 7

What are the three major groups of Acetylcholinesterase inhibitors?

Answer 7

Short & medium duration inhibitors which are reversible

Long duration inhibitors are often irreversible and highly toxic

Question 8

What types of drugs are used to treat Myasthenia Gravis?

Answer 8

Acetylcholinesterase inhibitors, which enhance cholinergic transmission to prevent muscle weakness

Question 9

What is Myathenia Gravis?

Answer 9

It’s an auto-immune disease causing a decreased number of functional postsynaptic nicotinic receptors on endplatesThis condition is characterised by muscle weakness

Question 10

What do organophosphates act like? And how does this get corrected

Answer 10

Organophosphates like Dyflos act as irreversible anti-cholinesterases, where the dyflos covalently binds to the serine residue for the active site. Must give pralidoxime within 30 minutes before the damage can be undone, otherwise the cell destroys the affected enzymes

Question 11

What is Neostigmine?

Answer 11

A medium duration Antiocholinesterase inhibitor which acts at the NMJ

Question 12

What rate does ACh-E hydrolyse Ach in the synaptic cleft?

Answer 12

25,000 molecules per second, per single ACh-E site

Question 13

Describe a nicotinic receptor

Answer 13

Nicotinic receptors are pentameric ligand gated ion channels that allow for rapid depolarisation of muscle fibres(It takes two Ach molecules to open the channel)

Question 14

What is agonist-induced receptor desentization?

Answer 14

It’s a process whereby the receptor decreases its response to a signalling molecule when it is present in high concentration.This occurs at nicotinic receptors at the NMJ to stop too much Na+ from entering the cell, and this prevents it from swelling.When the agonist binds for too long (due to it not being broken down by Ach-E), it goes to a closed desensitized state to stop the influx of Na+ (and thus preventing cell swelling and death due to water following Na+ into the cell)

Question 15

What is the Nicotinic agonist we can use clinically which will only act at the NMJ?

Answer 15

Suxamethonium, this drug induces receptor desensitzation

Question 16

What are 3 Nicotinic-R blokers we can use to cause competive antagonsism in the NMJ as an alternative to suxamethonium

Answer 16

Tubocurarine, Gallamine, Pancuronium