Drugs and synaptic transmission

Question 1

Describe the general process of what happens at a synapse

Answer 1

A nerve is activated caused by the opening of voltage gated sodium ion channels (concentrated in the nodes of Ranvier).

1. The first step is the nerve making the chemical that is going to be released. A precursor molecule is produced. The nerve will make the chemical within the cells.
2. This precursor is then converted to a transmitter.
3. The storage of the chemical in organelles called vesicles.
4. There are some metabolites on the transmitter.
5. The sodium ion channels maintain depolarisation. E.g pain transmission can be inhibited by anaesthetics such as lignocaine that inhibit sodium ion channels
6. Influx of calcium ions by voltage gated calcium ion channels. E.g neuronal calcium ion channel blockers such as Eg ω-conotoxin analogue Ziconotide
7. The vesicle fusing with the membrane so the neurotransmitter can to be released. Get a depolarisation sufficient to open up voltage gated calcium channels.
8. Here is the receptor, the chemicals bond. Opening of receptors.
9. The transmitter needs to be removed, so it can be taken up by other cells.
10. Or taken back up into the terminal.
11. Or metabolised by something outside the cell

Question 2

Give a brief overview of SNARE proteins and what calcium ions do in the synapse

Answer 2

• SNARE proteins bring the vesicle containing the chemical close to the membrane -> the membranes fuse together, and a pore opens releasing the chemical.
• The influx of calcium increases the likelyhood of the collisions between the vesicles and the membrane, stabillising the activity of the two proteins coming together allowing the membrane pore to open.

Question 3

Describe in detail how vesicles bond to membranes

Answer 3

• There are two main V-SNARES: synaptobrevin. Snaptobrevin interacts with the t-snare (the synaxin 1 and snap 25).
• The synaptobrevin interacts with the t-snares on the membrane.
• Here we have the vesicle and the V-SNARES (full name in diagram) associated with them. These V-SNARES (synaptobrevin) interact with the Target 1 SNARE (which has two subunits Syntaxin-1 and SNAP 25) on the surface of the membrane.
• The synaptotagmin has bound to calcium ions, this then wants to bind to the phospholipids on the membrane.
• When these come together it pulls them tight to the membrane forming a SNAREpin – a complex between the V-SNARE and the T-SNARES. Bringing the vesicle tight and close to the membrane.
• The calcium binds to a receptor on the vesicle called synaptotagmin which stabilises the SNAREpin and causes the membrane to kink in the last diagram, allowing the membrane to open.
• This process is called vesicular fusion.
• Some toxins Botulinum toxin (Peptidase) work because they destroy the SNARE proteins in the cholinergic nerve. The toxins consist of two parts: one binds to a choline transporter - allowing the other degradative bits to get into the cell which degrade the V-SNARES or Target 1 SNARE. The second breaks down the SNAREpin region.
• Phospholipase also degrade SNAREpins.

Question 4

In cholinergic transmission what enzyme produced acetylcholine from choline and Acetyl Coenzyme A?

Answer 4

Choline acetyltransferase

Question 5

What happens at a cholinergic synapse?

Answer 5

The action potential arriving at the synaptic bulb causes voltage gated ion calcium ion channels to open, and so calcium ions diffuse into the synaptic bulb.
2. Calcium ions cause vesicles (containing acetylcholine) to fuse with presynaptic membrane, and acetylcholine is released by exocytosis (requiring ATP) into the synaptic cleft.
3. Acetylcholine binds to the receptor sites on the sodium ion channels in postsynaptic membrane, causing the channels to open and sodium ions to diffuse into postsynaptic neurone.
4. Presence of sodium ions creates an excitatory postsynaptic potential (EPSP), which will summate to generate an action potential, which travels down the postsynaptic neurone.
● Acetylcholinesterase hydrolyses acetylcholine into ethanoic acid and choline to prevent continual transmission of signals. Ethanoic acid and choline recycled.

Question 6

Describe Drug Modulation in cholinergic neurones

Answer 6

Hemicholinium – this drug directly inhibits the choline uptake.
Vesamicol – this prevents acetylcholine being directly stored the vesicles, it displaces it from the vesicle.
Toxins – these effect the vesicular binding process (such as botox)
Cholinesterase inhibitors – shorting acting, medium acting and irreversible (found in insecticides). These raise acetylcholine levels in the synaptic cleft

Question 7

How is noradrenaline taken up into the neurone?

Answer 7

Unlike acetylcholine, noradrenaline is taken up into the neurone by a neuronal transport (uptake 1) or taken up into other tissues (by uptake 2).

Question 8

How is noradrenaline made?

Answer 8

1. Tyrosine is converted to Dihydroxyphenylalanine (DOPA) (created by the enzyme tyrosine hydroxylase). This is the rate limiting enzyme.
2. DOPA is converted to dopamine (by DOPA decarboxylase).
3. DOPA decarboxylase is then converted to Dopamine Beta hydroxylase (found in vesicles and cytoplasm) which then forms noradrenaline.
4. In adrenal glands noradrenaline is coverted to adrenaline (can also work on adrenergic receptors). These two products can metabolise Phenylethanolamine and N-methyltransferase