Drug and synaptic transmission

Question 1

What are the main events which occur during synaptic transmission?

Answer 1

Synthesis
Storage
Release
Inactivation
Reuptake

Question 2

General mechanism of uptake

Answer 2

1. Uptake of precursor molecule
2. Precursors converted into transmitter
3. 3 and 4, the transmitter has two fates, it may be metabolised or packaged into vesicles
   a. Uptake of transmitter usually driven by co-uptake of Na+ into vesicle
4. Depolarisation of nerve driven by voltage gated sodium channel openings. Depolarisation sweeps down the nerve and when it gets to the nerve terminal, depolarisation is sufficient to open the voltage gated calcium channels. Membrane becomes depolarised and allows an influx of calcium
5. Exocytosis occurs where there is a fusion of vesicles with the membrane and depositing their contents
6. Receptor on the target cell are bounded to the contents
7. Neurotransmitter is taken up and unmetabolized into another cell
8. There is a receptor on the presynaptic membrane to which the transmitter can bind and activate causing inhibition(negative feedback pathways) by usually GCPRS that reduce activity of Ca2+ channels
9. Enzymes are present in the synaptic cleft that break down transmitter
   If the neurotransmitter is unmetabolized, it is recycled

Question 3

How does repolarisation occur?

Answer 3

There are a lot of potassium channels in nerve terminal which cause membrane potential to become hyperpolarised again

Question 4

What is vesicle fusion?

Answer 4

Vesicle fusion is the concentrated interaction of SNARE proteins

Question 5

Where are SNARE proteins located?

Answer 5

Some SNARE proteins are on the plasma membrane and others on vesicle membrane

Question 6

What are 2 snare proteins able to do?

Answer 6

2 snare proteins are able to come together to interact which allows the vesicle to fuse and deposit its content

Question 7

What are the three steps involved in snare proteins and their interactions?

Answer 7

Docking, fusion and release

Question 8

What are V-snares called?

Answer 8

V-snares are called synaptobrevin and synaptogamin

Question 9

Mechanism of snare proetins

Answer 9

• In absence of Ca2+ or any stimulation of the nerve, synaptogamin stops synaptobrevin from interacting with anything else
• Synaptogamin is a calcium binding protein
• Upon depolarisation you get an influx of Ca2+
• Calcium binds with synaptogamin and this complex dissociates off from synaptobrevin
• Synaptobrevin forms a complex with t-SNARE which effectively pulls vesicle into membrane-SNAREpin

SNAREpin allows transmitter to be released and has a finite lifetime and then breaks down

Question 10

How can vesicles be recycled?

Answer 10

Vesicle can be recycled by taking up more transmitter and being re-used

Question 11

What does Botulinum toxin do?

Answer 11

Degrades v-SNARES

Question 12

Mechanism of Botulinum toxin

Answer 12

Binds to certain glycoproteins found on cholinergic neurones

Question 13

How is botulinum toxin produced?

Answer 13

Produced by anaerobic bacterium clostridium botulinum

Question 14

What is the minimum lethal dosage of Botulinum toxin?

Answer 14

Minimum lethal dosage in mice is 10^-12 g

Question 15

What else is botulinum toxin similar to?

Answer 15

Similar to diptheria and tetanus toxins

Question 16

What does the first subunit do?

Answer 16

1-binds to a glycoprotein on cholinergic neurones allowing toxin entry

Question 17

What does the second subunit do?

Answer 17

Produces cellular affect which include cleavage of SNAP 25 and synaptobrevin

Question 18

How us botulinum toxin destroyed?

Answer 18

Toxin is destroyed by heating >85 degrees Celsius for longer than 5 minutes

Question 19

What type of nerves are cholinergic neurones?

Answer 19

Parasympathetic nerves

Question 20

What does cholinergic neurones do?

Answer 20

Uptake of choline by a sodium dependant mechanism

Question 21

How is choline modified?

Answer 21

• Choline is acetylated by choline acetyl transferase which creates acetylcholine in one step process
• Then Ach is packaged or modified by cholinesterase which breaks it down very rapidly

Question 22

Where is cholinesterase’s found?

Answer 22

Cholinesterase’s found on cell membrane, in intracellular space, on other cells and on the nerves themselves
Ach broken down very quickly

Question 23

What happens upon depolarisation of the membrane?

Answer 23

• Upon depolarisation of the membrane, Ca2+ will come in which causes the fusion of vesicles
• You get fusion of a lot of vesicles which will deposit their contents
• Ach can then bind to its receptor but has a short lasting effect due to the cholinesterase’s

Acetate gets taken off and the choline is available again to be taken up again

Question 24

What does Hemicholinium do ?

Answer 24

Hemicholinium can block the cholinergic uptake

Question 25

What does Vesamicol do?

Answer 25

Vesamicol stops the uptake into the vesicle

Question 26

What type of nerve is adrenergic neurones?

Answer 26

Sympathetic nerves

Question 27

What is the rate limiting step in adrenergic neurones?

Answer 27

Uptake of tyrosine

Question 28

Modification of Tyrosine

Answer 28

Tyrosine is then converted into noradrenaline which is a multi-step process

Question 29

What happens upon depolarisation of the adrenergic neurones?

Answer 29

• Upon depolarisation you get Ca2+ influx which causes release of noradrenaline
• The noradrenaline interacts with its receptors which are GPCR
• No enzymes that break down noradrenaline so effect is much longer lasting
Response terminated by uptake of noradrenaline into other cells or the high affinity uptake by the noradrenaline uptake mechanism

Question 30

Where is phenylethanolamine N-methyltransferase (PNMT)found?

Answer 30

Phenylethanolamine N-methyltransferase is found in adrenal gland

Question 31

What does Reserpine do?

Answer 31

Stops the uptake mechanism

Question 32

What does Guanethidine do?

Answer 32

Depletes vesicles

Question 33

What does CDI?

Answer 33

Inhibit the pumping mechanism that takes noradrenaline into the cell, so concentration of noradrenaline increases

Question 34

What does ATE do?

Answer 34

get taken up by this mechanism and compete with noradrenaline. Once they’re inside the neurone, they displace norandrenaline from the vesicle

Question 35

What do MOA inhibitors do?

Answer 35

• MOA inhibitors-inhibit the enzymes that breakdown noradrenaline

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