2. Acetylcholine & Amino acids

what is that

Acetylcholine (ACh)

Significance of Acetylcholine (ACh) as an NT

The first molecule to be implicated as a NT

What is the history of Acetylcholine (ACh) as an NT

Synthesis of ACh occurs where

Synthesis happens in the cytosol of the nerve terminus

ACh is a combination of what 2 molecules

Acetyl CoA & Choline

How is ACh synthesised

What transfers the acetate ion from Acetyl CoA to choline

ChAT (Choline acetyltransferase)

(ChAT tells Acetyl to chat to choline)

What transports ACh into synaptic vesicles for storage

Vesicular ACh Transporter (VAChT)

Where is VAChT located?

VAChT is embedded in the membrane of synaptic vesicles.

How does VAChT move ACh into vesicles?

VAChT uses a proton (H⁺) gradient established by a vesicular proton pump to drive ACh uptake into vesicles.

Acetylcholine can bind to what receptor type(s)

Ionotropic: Nicotinic receptor

Metabotropic: Muscarinic receptor

The structure of the nicotinic ACh receptor channel is made up of how many subunits

Receptor is made of 5 subunits: 2α, β, γ, δ

How many binding sites for ACh does each Nicotinic ACh receptor (ionotropic) have

Each nAChR complex has 2 binding sites for ACh

On what subunits does ACh usually bind to nicotinic receptors

Mostly on α-subunits, though partial involvement of δ and γ subunits

Why can’t calcium ions go through the nicotinic ACh receptor

They’re too big

What ion moves when the nicotinic ACh receptor opens

There is an influx of Na+

Agonist vs antagonist

Name 2 agonists to the nicotinic AChR (acetylcholine receptor)

Acetylcholine is the endogenous agonist

Nicotine is an agonist of ACh ionotropic receptor (a plant alkaloid identified in 1914)

Name an antagonist to the nicotinic AChR (acetylcholine receptor)

α-bungarotoxin is an antagonist of ACh ionotropic receptor (from snake venom)

How many different Muscarinic AChRs are there - name them

5: M1, M2, M3, M4, M5

There are 5 different mAChRs that can activate different G proteins that link to different signalling systems. Which of the 5 activate which G proteins which link to which signalling systems

M1, M3, M5: Activate phospholipase C (PLC) via G_o or G_q

M2, M4: Inhibit adenylate cyclase via G_i & stimulate a K+ channel via G_s

Where in the body are MAChR found & what are they doing there

mAChR present in striatum and in peripheral nervous system. They also mediate autonomic functions acting on heart, smooth muscle and exocrine glands

Name an agonist that binds to Muscarinic AChRs

Muscarine: Fungal alkaloid that binds with high affinity

Fill this in and explain

• Atropine:

  • Non-selective muscarinic antagonist

  • Blocks M1, M2, and M3 → affects brain, heart, and glands

  • Broad parasympathetic-blocking effects (dry mouth, increased heart rate, CNS effects)

• Pirenzepine:

  • Selective M1 antagonist

  • Blocks M1 in the brain (and stomach’s gastric glands)

• Himbacine:

  • Blocks M2 (heart)

  • Mainly affects heart rate (can prevent parasympathetic slowing of the heart)

How is ACh inactivated

Enzymatic degradation - Degraded by acetylcholinesterase in synaptic cleft where ACh is at high concentration

Catalytic rate of acetylcholinesterase

10⁴ – 10⁵ mols per sec

One of the most rapid enzymes known

What happens when ACh is inactivated

Choline is taken back up into the nerve terminal by high affinity Na+- dependent uptake system

Name some drugs that inhibit Acetylcholinesterase

• Sarin nerve gas – lethal dose is 0.5 mg (weapon of war)

• Organophosphates – used in insecticides (can’t stop contraction of muscles - kills the insects)

• Neostigmine, donezepil (used in treatment of Alzheimer’s disease as ACh is depleted at junctions in the brain)

At what location is ACh degraded

In the synaptic cleft

Name an ACh neurotransmission disease

Myasthenia gravis

What does Myasthenia gravis present as

Muscle weakness

What kind of disease is Myasthenia gravis

Autoimmune disorder - Patients’ sera contain antibodies directed against their own nicotinic AChRs → decreased number of functional AChRs on muscle cells → defective neuromuscular transmission leading to muscle weakness

What can be used as treatment against Myasthenia Gravis

Neostigmine treatment