Drug and synaptic transmission Flashcards
What are the main events which occur during synaptic transmission?
Synthesis Storage Release Inactivation Reuptake
General mechanism of uptake
- Uptake of precursor molecule
- Precursors converted into transmitter
- 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 - 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
- Exocytosis occurs where there is a fusion of vesicles with the membrane and depositing their contents
- Receptor on the target cell are bounded to the contents
- Neurotransmitter is taken up and unmetabolized into another cell
- 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
- Enzymes are present in the synaptic cleft that break down transmitter
If the neurotransmitter is unmetabolized, it is recycled
How does repolarisation occur?
There are a lot of potassium channels in nerve terminal which cause membrane potential to become hyperpolarised again
What is vesicle fusion?
Vesicle fusion is the concentrated interaction of SNARE proteins
Where are SNARE proteins located?
Some SNARE proteins are on the plasma membrane and others on vesicle membrane
What are 2 snare proteins able to do?
2 snare proteins are able to come together to interact which allows the vesicle to fuse and deposit its content
What are the three steps involved in snare proteins and their interactions?
Docking, fusion and release
What are V-snares called?
V-snares are called synaptobrevin and synaptogamin
Mechanism of snare proetins
- 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
How can vesicles be recycled?
Vesicle can be recycled by taking up more transmitter and being re-used
What does Botulinum toxin do?
Degrades v-SNARES
Mechanism of Botulinum toxin
Binds to certain glycoproteins found on cholinergic neurones
How is botulinum toxin produced?
Produced by anaerobic bacterium clostridium botulinum
What is the minimum lethal dosage of Botulinum toxin?
Minimum lethal dosage in mice is 10^-12 g
What else is botulinum toxin similar to?
Similar to diptheria and tetanus toxins
What does the first subunit do?
1-binds to a glycoprotein on cholinergic neurones allowing toxin entry
What does the second subunit do?
Produces cellular affect which include cleavage of SNAP 25 and synaptobrevin
How us botulinum toxin destroyed?
Toxin is destroyed by heating >85 degrees Celsius for longer than 5 minutes
What type of nerves are cholinergic neurones?
Parasympathetic nerves
What does cholinergic neurones do?
Uptake of choline by a sodium dependant mechanism
How is choline modified?
- 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
Where is cholinesterase’s found?
Cholinesterase’s found on cell membrane, in intracellular space, on other cells and on the nerves themselves
Ach broken down very quickly
What happens upon depolarisation of the membrane?
- 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
What does Hemicholinium do ?
Hemicholinium can block the cholinergic uptake
What does Vesamicol do?
Vesamicol stops the uptake into the vesicle
What type of nerve is adrenergic neurones?
Sympathetic nerves
What is the rate limiting step in adrenergic neurones?
Uptake of tyrosine
Modification of Tyrosine
Tyrosine is then converted into noradrenaline which is a multi-step process
What happens upon depolarisation of the adrenergic neurones?
• 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
Where is phenylethanolamine N-methyltransferase (PNMT)found?
Phenylethanolamine N-methyltransferase is found in adrenal gland
What does Reserpine do?
Stops the uptake mechanism
What does Guanethidine do?
Depletes vesicles
What does CDI?
Inhibit the pumping mechanism that takes noradrenaline into the cell, so concentration of noradrenaline increases
What does ATE do?
get taken up by this mechanism and compete with noradrenaline. Once they’re inside the neurone, they displace norandrenaline from the vesicle
What do MOA inhibitors do?
• MOA inhibitors-inhibit the enzymes that breakdown noradrenaline
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