Synaptic Transmission Flashcards
How are vesicles able to fuse to the cell membrane?
With the help of SNARE proteins on the surface of the vesicles and on the cell membrane.
* SNARE proteins bring the vesicle containing the chemical close to the membrane -> the membranes fuse together, and a pore opens releasing the chemical.
Describe how SNAREs help fusion of vesicles with the cell membrane.
There is a protein called Synaptotagmin covering the v-SNARE e.g synaptobrevin, stopping any interactions in absence of calcium ions. With the influx of Ca2+, the Synaptotagmin is removed due to binding of Ca 2+ ions, causing dissociation from the v-SNARE and allowing the v-SNARE to bind to the t-SNARE. This creates a ‘SNAREpin’, which is a coiled v and t-SNARE complex. This pin causes the movement of vesicles close to the membrane, allowing deformation of the vesicles and thus exocytosis of the vesicle’s contents.
What are the functions of the two subunits of Botulinum?
Some toxins Botulinum toxin (Peptidase) work because they destroy the SNARE proteins (e.g synaptobrevin, SNAP 25) in the cholinergic nerve. The toxins consist of two parts: one binds to a choline transporter - allowing the other degradative areas to get into the cell which degrades the V-SNARES or Target 1 SNARE. The second breaks down the SNAREpin region.
EXAMPLE:
Botulinum A cleaves SNAP 25
Botulinum B cleaves SYNAPTOBREVIN (VAMP)
Botulinum C cleaves SNAP 25 / SYNTAXIN
Describe synaptic transmission in cholinergic neurones.
- Choline (precursor) is taken up into the neurone. The choline is then converted to acetylcholine via choline acetyl transferase.
- Then, acetylcholine is either transferred to a vesicle (through a Vesicular Monoamine Transporter (VMAT) - ATP is required) or converted back to choline.
- Voltage-gated calcium ion channels open causing an influx of calcium ions due to sufficient membrane depolarisation.
- Then, via the SNAREs, the vesicle is fused to the cell membrane and the acetylcholine is released into the synaptic cleft. Calcium ions causes many vesicles (containing acetylcholine) to fuse with presynaptic membrane, and acetylcholine is released by exocytosis (requiring ATP) into the synaptic cleft.
- The acetylcholine could bind to postsynaptic receptors i.e nAChRs, triggering an effect on the postsynaptic neurone. 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. Presence of sodium ions creates an excitatory postsynaptic potential (EPSP), which will summate to generate an action potential, which travels down the postsynaptic neurone.
- Acetylcholine could also be broken down by enzymes (cholinesterases) in the synaptic cleft or recycled with choline available for reuptake. Ach broken down very quickly hence why the response is transient.
List some cholinesterase inhibitors, and mention how long they last.
Short lasting- edrophonium
Medium acting- Neostigmine, physostigmine
Irreversible- Parathion, ectothiophate
These inhibitors raise acetylcholine levels in the synaptic cleft
Describe synaptic transmission in adrenergic neurones.
- Tyrosine (precursor) is brought into the neuron - tyrosine uptake is the rate-limiting step. The tyrosine is then converted to noradrenaline.
- Then, noradrenaline is transferred to and packaged in a vesicle (through a Vesicular Monoamine Transporter (VMAT)).
- Via the SNAREs, the vesicle is fused to the cell membrane and the noradrenaline is released into the synaptic cleft. Triggered by movement of calcium ions through voltage-gated calcium ion channels - triggered by sufficient membrane depolarisation.
The noradrenaline could bind to postsynaptic receptors , triggering an effect on the postsynaptic neurone. - It could be re-uptaken back into the presynaptic neurone via the Neuronal Transporter (NET) or the extraneuronal monoamine transporter (EMT).
List some drugs that affect adrenergic neurons.
Competing with Noradrenaline:
- Amphetamine
- Tyramine
- Ephedrine
Competes with noradrenaline to be inside vesicle.
Acting on the NET:
- Cocaine
- Desipramine
- Imipramine
Reduced reuptake of noradrenaline so noradrenaline builds up
Describe the synthesis and metabolism of Noradrenaline.
1) Tyrosine is converted into Dihydroxyphenylalanine (DOPA) by Tyrosine Hydroxylase - rate-limiting enzyme
2) DOPA is converted into Dopamine by DOPA decarboxylase
3) Dopamine is converted into Noradrenaline by Dopamine-β-hydroxylase
Describe the general process of what happens at a synapse
- A precursor molecule is synthesised or taken up.
- This precursor is then converted to a transmitter which is either metabolised or packaged into vesicles.
- The storage of the chemical in organelles called vesicles. Uptake of transmitter usually driven by co-uptake of Na+ into vesicle
- The sodium ion channels cause depolarisation of the membrane. Get a depolarisation sufficient to open up voltage-gated calcium channels.
- Influx of calcium ions by voltage gated calcium ion channels.
- The vesicle fusing with the membrane so the neurotransmitter can be released by exocytosis.
- Binds to receptors on postsynaptic membrane
- The transmitter needs to be taken back up into the terminal if unmetabolised or metabolised by cholinesterases
Describe drug modulation in cholinergic neurons
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 affect the vesicular binding process (such as botox)
Why does noradrenaline have a longer lasting effect than acetylcholine?
Since it has no enzymes that break it down, it will have a prelonged effect on the synapse compared to Acetylcholine (which does get broken down). Response terminated by noradrenaline uptake.
