Drugs And Synaptic Transmission Flashcards
The different formation of transmitter, storage, vesicular fusion and release, termination of chemical transmission.
- Uptake of precursor molecule
- Precursors are converted to transmitter
- Packaged into vesicles
o Where, sodium assisted uptake - very little sodium inside vesicle mechanism facilitated entry by Na+ influx
o Transmitter taken up into vesicles
o Can have vesicle random collisions of vesicles with membrane – miniature blimps as in myaesthesia gravis - Or when precursors converted into transmitters, can be metabolized
- After step 3, the activated response causes depolarisation of the nerve
o This depolarisation is driven by voltage gated Na+ channels open
o Depolarisation goes down the nerve, and when at nerve terminal, - The membrane depolarisation is sufficient to open up voltage gated Ca2+ channel to allow influx of Ca2+ down gradient
- Fusion of vesicles fusing with the membrane and depositing the contents
o random collisions releasing vesicle which releases molecules
o Deposited transmitter but a chemical nothing without receptor - Receptor on target cell – produces biological response in cell
- Taken up unmetabolised, by another cell type
- Receptor on nerve that the transmitter can activate – which causes inhibition
o negative feedback pathway – to stop releasing transmitter
o This pre-synaptic inhibition by signals being released from usually GPCR which reduced activity of calcium channels - Metabolised break down
- Taken up unmetabolised back into cell where it is metabolised or repackaged
Describe how cholinergic neurones synthesize acetylcholine, how it is released and how the response is terminated by enzymatic degradation.
1) Uptake of Choline, by a Na+ dependant mechanism
2) Choline acetyltransferase transfers acetyl group from acetyl CoA onto choline to make acetyl choline
3) This is packaged or modified by cholinesterase which breaks down acetylcholine
4) Acetylcholine is very short-lived
5) Upon depolarisation of membrane, Ca2+ comes in, and causes fusion of vesicles, which bins to Synaptogamin which allows synaptobrevin to interact with T-SNARES and so fusion of many vesicles
6) This deposits contents acetylcholine interacts with receptors
7) Short effect of acetylcholine as there is cholinesterase everywhere, which degrade neurotransmitter rapidly
ACh is synthesised by—
Choline + Acetyl CoA ---------- Acetylcholine + CoA
Choline acetyltransferase (ChAT)
- We get choline from our diet (liver, fish) and it is also taken up by the choline carrier at the presynaptic terminal.
- Acetyl CoA is produced by cellular respiration.
Describe how adrenergic neurones synthesize noradrenaline, how it is released and how the response is terminated by re-uptake and degradation.
The first step, with tyrosine hydroxylase is the rate limiting step
1) Uptake of tyrosine molecule
2) Converted to noradrenaline –
Formation and Metabolism
Tyrosine converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.
DOPA converted to Dopamine by DOPA decarboxylase
Dopamine taken up into vesicle which creates the primary transmitter noradrenaline by dopamine beta-hydroxylase
Noradrenaline converted to adrenaline in adrenal gland mainly
Noradrenaline can be metabolised by 2 main enzymes; monoamine oxidase and catechol-o-methyl transferase
3) Packed into vesicles
4) Depolarise membrane and Ca2+ influx
5) Ca2+ binds to Synaptogamin, which allows synaptobrevin to interact with T-SNAREs (syntaxin-1 and SNAP-25) and get fusion
6) Interact with receptor
7) Adrenal receptors are GPCR
8) Noe located pre-synaptically
9) No enzyme breaking own noradrenaline – longer lasting effects than Ach
10) Response terminated by uptake into another cells OR
11) High affinity uptake by noradrenaline uptake mechanism
12) Or Noradrenaline re-uptake pathway
tyrosine hydroxylase (in cytoplasm) dopamine decarboxylase (cytoplasm) Tyrosine + DOPA ------------------- DOPA decarboxylase -----------Dopamine
dopamine hydrolase (in vesicles) ---------------------- Noradrenaline ---------------- Adrenaline
How various drugs alter chemical transmission in adrenergic and cholinergic nerves
• Block cholinergic uptake by Hemicholinium
• Vesamicol – stops uptake into vesicles
• Botulinum and diphtheria toxins only target cholinergic neurones which affects this process.
• Cholinesterase Inhibitors – cholinesterase keeps Ach concentration low and short lasting, an inhibitor will increase the amount of Ach in cholinergic receptor and continues stimulation
o 3 types of cholinesterase inhibitors
o Short acting: edrophonium
o Medium acting neostigmine
o Irreversible: insecticide Parathion
• Reserpine – stop uptake pump
• Guanethidine- depletes vesicles causing chemical to be release
• Cocaine, desipramine, Imipramine- inhibit the pumping mechanisms which take noradrenaline up into cell
o Noradrenaline concentration increases if cocaine taken
o Cocaine inhibits and amphetamine etc. affect reuptake mechanism
• Amphetamine, tyramine, ephedrine – don’t inhibit pump directly, they are taken up by mechanism and because taken up, compete with noradrenaline
o competes with noradrenaline
o Once inside neurone, displace noradrenaline from vesicles and so more noradrenaline leaked out
• Tranylcypromine inhibit enzymes that break down noradrenaline
• MAO inhibitor: Used as anti-depressant
Drugs that inhibit voltage gated Na+ channels
If you block the voltage-dependent Na+ channels, it will prevent AP generation along the axon.
• Therefore, it will stop the pre-synaptic terminal from being depolarised (no Ca2+ will can influx) and this synaptic transmission will be inhibited.
• Na+ channel blockers bind to and block Na+ entering the cell.
• Examples of uses of such drugs include—
• Local anaesthetics: e.g. lignocaine, which prevents AP conduction and synaptic transmission in sensory nerves so stops inputs to brain that code for pain. Hence the individual has no sensation of pain.
Drugs that inhibit voltage gated Ca2+ channels
- Blockers of synaptic transmission.
- If you block the voltage dependent Ca2+ channels it will prevent Ca2+ influx
- The neurotransmitter will not be released - this inhibits synaptic transmission.
- Examples of these drugs include analgesics, e.g. ziconotide.
Neurotransmitter is released..
- Action potentials reach axon terminals
- Voltage-gated Ca2+ channels open (neuronal type p, q or n)
- Influx of calcium causes synaptic vesicles to fuse with the membrane
- Interaction of SNARE proteins
- Vesicle fusion after interaction with SNARE proteins
- Some SNARE protein on vesicle membrane and cell membrane
- Both come together and interact like Velcro
- Vesicle then recycles
SNARE proteins
- Two SNARE proteins
- Vesicle-SNARE and Target-SNARE
- V-SNAREs are synaptobrevin (aka vesicle-associated membrane protein) and Synaptogamin on vesicle membrane
- T-SNAREs are Syntaxin-1 and SNAP25 on cell membranes
- Absence of stimulation of nerve – Synaptogamin stops synaptobrevin from interacting with anything else
- Influx of calcium, Ca2+ binds to Synaptogamin, (like tropomyosin).
- This Synaptogamin-Ca complex dissociates the vesicle from synaptobrevin
- Synaptobrevin then forms a complex with T-SNARE called SNARE pin
Pharmacological effects
• Clostridium botulinum bacteria produces a toxin which causes botulism. The toxin enters the terminals and degrades Ach- containing vesicles, so the ANS and motor fibres are inhibited. Botox stops release of Ach to facial muscles
• Botox:
• degrades V-SNAREs
• binds to glycoproteins found on cholinergic neurones only
• very low levels of botulinum toxin are used to produce local paralysis (cosmetic/clinical uses)
• Two subunits:
1) Clamps on cholinergic neuron binding to specific glycoprotein
2) Second subunit then enters the cell and degrades SNARE proteins
• Beta-bungarotoxin is a type of snake venom, - breaks down T-SNARE
• Affecting cholinergic transmission
• which prevents Ach release,
In-activation and Re-uptake
NA removal is different to Ach, it is not enzymatic in the synaptic cleft. Rather, NA is removed by re-uptake unchanged back into the pre-synaptic terminal.
NA is then recycled back into vesicles OR metabolized by monoamine oxidase (MAO) in neurons or catechol-O-methyltransferase (COMT) in non-neuronal sites (e.g. adrenal medulla).
