Drugs and Synaptic Transmission

Question 1

How are neurotransmitters released?

Answer 1

1. Action potentials reach axon terminals
2. Voltage-gated Ca2+ channels open
3. Ca2+ binds to sensor protein in cytoplasm
4. Ca2+-protein complex stimulates fusion and exocytosis of neurotransmitter

Question 2

How does the vesicle fuse with the membrane?

Answer 2

When we get an increase in calcium coming through those calcium channels, synaptotagmin binds the calcium, and then it has an increased affinity for membrane phospholipids
So now it binds to the phospholipids
In addition it has a reduced affinity for the v-SNARE, so normally its kind of inhibiting the v-SNARE action but with the rise in calcium the v-SNARE is now released and can interact with a similar protein
The v-SNARE interacts with the t-SNARE, the two types of SNAREs are brought into close proximity and they fuse to become a SNARE pin which pulls the vesicle to the membrane
The membrane then deforms and the contents are released

Question 3

What can degrade the synaptic transmission mechanism?

Answer 3

Botulinum toxin is produced by the anaerobic bacterium Clostridium botulinum
(Minimum lethal dose in mice is 10^-12 g)
Similar to dipheria and tetanus toxins
Two subunits
1-binds to a glycoprotein to cholinergic neurones allowing toxin entry
2-produces cellular effects below:
Botulinum A cleaves SNAP25
Botulinum B cleaves SYNAPTOBREVIN (VAMP)
Botulinum C cleaves SNAP25/SYNTAXIN
Botulinum D cleaves SYNAPTOBREVIN (VAMP)
Botulinum E cleaves SNAP25
Botulinum F cleaves SYNAPTOBREVIN (VAMP)
Botulinum G cleaves SYNAPTOBREVIN (VAMP)
Tetanus cleaves synaptobrevin (VAMP)
The toxin is destroyed by heating >85’C for longer

Question 4

How do cholinergic neurones work?

Answer 4

The uptake mechanism is that choline is taken up along with sodium Na+
Choline is converted to acetylcholine though the enzyme choline acetyl transferase
Acetylcholine is stored in vesicles then you get your calcium-dependent fusing via the SNARE proteins
Acetylcholine will interact with its receptors wither the ligand gated ion channels (nicotinic) or the G-protein coupled receptors (muscarinic)
There are some auto-receptors that reduce nervous activity on the nerve terminal
Responses are always short acting because of the presence of choline esterases/acetylcholine esterases which break down acetyl choline and keep the signal responses brief

Question 5

How do drugs modulate cholinergic neurone?

Answer 5

This whole pathway can be modulated by hemicholinium that competes with choline for uptake
Vesamicol which stops uptake of acetylcholine into the vesicle
The different toxins mentioned earlier that stops the fusion of the vesicle and the deposit of its cargo
Cholinesterase inhibitors:
Edrophonium (short acting)
Neostigmine and Physostigmine (middle acting)
Parathion, dyflos (long acting)

Question 6

What are adrenergic neurones?

Answer 6

The starting point for creation of noradrenaline is the uptake of tyrosine through an uptake transporter
Tyrosine is enzymatically worked on to create noradrenaline, which is stored in the vesicles along with ATP
Noradrenaline, unlike acetylcholine, is not degraded by an enzyme in the cleft, but actually inactivated by take up into extra-neuronal cells or back into the neurones by an extra neuronal monoamine transporter (EMT)
There’s also an auto receptor that turns iff the activation and release of the noradrenaline

Question 7

How do drugs modulate adrenergic neurones?

Answer 7

Reserpine stops the uptake of noradrenaline into the vesicle
Guanethidine displaces it
Many drugs inhibit noradrenaline uptake through the transporter including:
Cocaine
Desipramine- antidepressant
Imipramine
There are also drugs which are taken up by the transporter and out competes the noradrenaline:
Amphetamine
Tyramine
Ephedrine
Other easy gen antidepressants that are mono inhibitors e.g. Isocarboxazid etc.