Drugs And Synaptic Transmission

Question 1

How are vesicles allowed to fused to the cell membrane?

Answer 1

It’s done with the help of SNARE proteins on the surface of the vesicles and on the cell membrane.

Question 2

Describe how SNAREs help fusion of vesicles with cell membrane.

Answer 2

There are v-SNAREs (vesicles-SNAREs, examples being VAMP or Synaptobrevin) on the vesicle’s surface, and there are t-SNAREs (target-SNAREs, examples being Syntaxin-1 and SNAP 25).
There is a protein called Synaptotagmin covering the v-SNARE, stopping any interactions. With the influx of Ca2+, the Synaptotagmin is removed, allowing the v-SNARE to bind to the t-SNARE. This creates a ‘SNAREpin’, which is a coiled coil v and t-SNARE complex.

Question 3

What are the functions of the two subunits of Botulinum?

Answer 3

The first subunit binds to a glycoprotein on cholinergic neurones, allowing toxin entry. The second subunit then produces cellular effects (ie. cleaving SNAREs).

Question 4

Describe synaptic transmission in cholinergic neurones.

Answer 4

Choline (precursor) is brought into the neurone. The choline is then converted to acetylcholine via choline acetyl transferase. Then, acetylcholine is either transferred to a vesicle (through a Vesicular Monoamine Transporter (VMAT) - ATP is required) or converted back to choline. Then, via the SNAREs, the vesicle is fused to the cell membrane and the acetylcholine is released into the synaptic cleft.
The acetylcholine could bind to postsynaptic receptors, triggering an effect on the postsynaptic neurone. It could also be broken down by enzymes (cholinesterases) in the synaptic cleft.

Question 5

List some cholinesterase inhibitors, and mention how long they last.

Answer 5

Short lasting- edrophonium
Medium acting- Neostigmine, physostigmine
Irreversible- Parathion, ectothiophate, dyflos

Question 6

Describe synaptic transmission in adrenergic neurones.

Answer 6

Tyrosine (precursor) is brought into the neurone. The tyrosine is then converted to noradrenaline. Then, noradrenaline is either transferred to a vesicle (through a Vesicular Monoamine Transporter (VMAT)) or converted into metabolites. Then, via the SNAREs, the vesicle is fused to the cell membrane and the noradrenaline is released into the synaptic cleft.
The noradrenaline could bind to postsynaptic receptors, triggering an effect on the postsynaptic neurone. It could be re-uptaken back into the presynaptic neurone via the Neuronal Transporter (NET). It could also be uptaken by another neurone via the extraneuronal monoamine transporter (EMT).
Since it has no enzymes that break it down, it will have a prelonged effect on the synapse compared to Acetylcholine (which does get broken down).

Question 7

List some drugs that affect adrenergic neurones.

Answer 7

Competing with Noradrenaline:

• Amphetamine
• Tyramine
• Ephedrine

Acting on the NET:

• Cocaine
• Desipramine
• Imipramine

Acting on the metabolites:
MOA inhibitors such as:
- Tranylcypromine
- Isocarboxazid

Acting on the vesicle:
- Guanethidine

Acting on the VMAT:
- Reserpine

Question 8

Describe the synthesis and metabolism of Noradrenaline.

Answer 8

1) Tyrosine is converted into Dihydroxyphenylalanine (DOPA) by Tyrosine Hydroxylase
2) DOPA is converted into Dopamine by DOPA decarboxylase
3) Dopamine is converted into Noradrenaline by Dopamine-β-hydroxylase

4) Then, the Noradrenaline can be converted into Adrenaline by Phenylethanolamine or N-methyltransferase2
Or, the Noradrenaline can be converted into Metabolites by Monoamine Oxidase or Catechol-O-Methyl Transferase.