Part 1

Question 1

How is acetylcholine synthesised?

Answer 1

Precursors Acetyl coenzyme A and Choline

Catalysed by choline acetyltransferase (ChAT)

Forms acetylcholine and coenzyme A

Question 2

How does ChAT work?
Is it in excess?
Is this the same for all neurotransmitters?

Answer 2

ChAT transfers the acetate ion from acetyl-CoA to choline

ChAT is specific to cholinergic neurones
It is present in the neuronal terminal in excess, i.e. if there are precursors, ACh will always be made because the enzyme is not saturated

No - in dopamine synthesis, the enzyme that converts tyrosine to L-DOPA is saturated by substrate. Giving more tyrosine would make more DA

Question 3

What types of receptors does ACh bind to?

Answer 3

Binds to postsynaptic or muscular receptors

• muscarinic (types M1 - M5)
• nicotinic receptors (different subtypes)

Question 4

How is acetylcholine inactivated/reuptaken?

Answer 4

The enzyme acetylcholinesterase breaks down ACh into choline and acetate

The choline is then taken back up and recycled to form ACh.
40-50% of the choline formed by ACh breakdown is take up into the presynaptic terminal by active, high affinity transporter specific to cholinergic cells

Question 5

Where are cholinergic pathways in the brain?

Answer 5

The basal forebrain contains two groups of cholinergic neurones:

1. Medial septal group
2. Nucleus Basalis group

The cholinergic pontomesenceophalon neurones project to the hindbrain, thalamus, hypothalamus and basal forebrain

They interact with other areas and neurones. 
Projections to cortical regions include 
- musculoskeletal 
- cognition
- memory 

Drugs can target different cholinergic paths to influence different things

Question 6

What is the neuromuscular junction?

How does ACh function here?

Answer 6

NMJ - chemical synapse between a motor neurone and skeletal muscle
Communication between these two cells is carrried out by acetylcholine

Release of acetylcholine is initiated by the arrival of an action potential propagating along the axon of the motor neuron

Depolarisation of the nerve ending opens calcium channels and calcium ion influx causes exocytosis of ACh

ACh binds to post synaptic (muscular) ligand gated ion channels which are nicotinic receptors.
The channel opens letting Na+ into the muscle cell thus causing depolarisation - excitatory signal

AP on membrane of skeletal muscle cell opens calcium channels allowing Ca2+ entry —> action potential generated leads to muscle contraction

Action of ACh in the NMJ is terminated by AChE

Question 7

What is an example of a disorder of the NMJ?

Answer 7

Myasthenia gravis:

• autoimmune condition where antibodies block or damage the nicotinic receptors in the NMJ
• ACh cant act to pass on AP from neurone to muscle
• dampening down of the signals ad results in muscles not contracting
• over time the muscles become weak

Question 8

How is myasthenia gravis treated?

Answer 8

Medicines aim to prevent the breakdown of acetylcholine in the synapse
E.g Pyridostigmine is an AChE inhibitor so prevents the breakdown of acetylcholine

These medicine tend to work better in mild disease where more receptors are still present for ACh to act on