1.9 PHYS - Synaptic Transmission and Neurotransmitters Flashcards
What are electrical synapses? (what special feature do they have and what does this allow them to do, where are they found, how big are the synaptic clefts compared to chemical synapses, what are the downsides to these types of synapses?).
They have gap junctions. Allow them to relay signals in a fast manner with no delay. Also allows them to be bidirectional.
They connect large groups of neurons. Found in cardiac and some types of smooth muscle.
Synaptic clefts are 3.5nm vs. 25nm (tiny).
Downside: channels are large and unselective.
What are the different steps of synaptic transmission at the neuromuscular junction (7-steps)?
- Action potential travels down neuron to terminal.
- Ca++ voltage-gated channels open and allow Ca++ into cell.
- Ca++ influx causes neurotransmitter release from presynaptic terminal into synaptic cleft.
- Neurotransmitter binds postsynaptic membrane receptors.
- Ligand-gated Na+/K+ channels are opened.
- Postsynaptic terminal is depolarized and action potential created in post synaptic neuron.
- Neurotransmitter is cleaned up from synaptic cleft (and sometimes recycled).
Neurotransmitters are released from vesicles from presynaptic neurons into the synaptic cleft. Where do these vesicles come from? Where are they produced? How do they end up in the terminal?
Vesicles are produced in the golgi in the soma of the presynaptic neuron.
After production these vesicles then travel down the neuron by way of microtubules until they reach their destination in the terminal of the presynaptic neuron.
Action potentials travel down the axon of presynaptic neurons, when they reach the terminal they activate voltage-gated Ca++ channels. Due to the low concentration of Ca++ in the neuron, this causes an influx of Ca++ into the cell. Why is Ca++ needed in the presynaptic neuron anyway? What does it do? (brief).
Calcium is necessary in the presynaptic terminal because it controls vesicle fusion and mobilization of synaptic vesicles.
What are the three steps of transmitter release from presynaptic neuron to postsynaptic neuron?
Targetting of the vesicle.
Discharge of transmitter by exocytosis.
Recycling of membrane.
(process is conserved from worms to humans)
What happens when the vesicles travel down the neuron via microtubules and reach the terminal? What protein is at play here, what happens to it?
Synapsins (substrate of cAMP-dependent protein kinase and Ca++/calmodulin-dependent protein kinase).
When non-phosphorylated: synapsins bind vesicles to actin filaments (microtubules) in the cytosol.
When phosphorylated: (due to Ca++ entry), synapsins release the vesicles, allowing them to move into “active zone”.
Once the vesicle is free of synapsin and the microtubule, what occurs next? What is the protein at play here, describe what happens to it (what does it bind etc.)?
Rab protein binds GTP and the vesicle.
Hydrolysis of GTP -> GDP could be part of targetting the vesicle to docking site (unkown).
Rab proteins are recycled into cytoplasm after vesicle is released.
Once the Rab protein targets the docking site and releases the vesicle, what happens next? What protein(s) are interacting here?
Vesicle proteins: VAMP, interact with membrane proteins: SNAP-25 and syntaxin. This interaction allows docking of the vesicle to the presynaptic membrane.
VAMP (on vesicle) + SNAP-25 (on membrane) = SNARE complex
What accessory protein is neccessary for the SNARE complex to fullfill its duty? How does this protein do this?
Munc18.
Required for exocytosis of synaptic vesicles.
Munc18 binds to synatxin before synaptobrevin binds and holds the SNARE complex together without it it would fall apart and vesicle would not dock correctly.
Clostridial neurotoxins such as tetanus and botulinum toxin can cause issues in the NMJ, explain which step in transmitter release they affect, and how they are affecting it?
Disrupt docking and priming.
Tetanus: targets and cleaves VAMP.
Botulinum toxins A, B, and C: cleave SNAP-25, VAMP, and synatxin, respectively.
What is alpha-latrotoxin, where does it come from, how does it disrupt neurotransmitter release?
A spider toxin.
Generates massive vesicle depletion and transmitter release.
Binds to neurexin (similar to syntaxin), enhances docking so vesicles cannot recycle, keeps SNARE complex together.
Now that we have the vesicle docked and ready to roll, how does the transmitter actually get released? What proteins are functioning here?
Ca++ enters the cell and binds to synaptotagmin (which is on the vesicle wall).
This binding triggers fusion of the vesicle with the terminal membrane, and release of the neurotransmitter.
Now that we have finally freed the vesicle, targetted the vesicle to the membrane, docked the vesicle, released the transmitter. What is the final step in the long complicated life of this vesicle? Where’s it headed to next? How does it break free of its confines with the presynaptic membrane?
A cytoplasmic ATPase, NSF protein, uses SNAP (unrelated to SNAP-25) to bind to the SNARE complex and unravel it.
This releases the vesicle so it can be free and recycled for another episode of its daily life.
What are the 4 criteria that a neurtransmitter must fulfill in order to be considered a neurotransmitter?
- Synthesized in neuron.
- Present in presynaptic terminal and released in significant amounts to produce a clear effect on postsynaptic neuron or effector organ.
- When tested exogenously, it behaves as it does endogenously.
- There is a specific way it is removed from synaptic cleft.
What happens to all the neurotransmitters after they are finished in the synaptic cleft?
They diffuse from presynaptic neuron into synaptic cleft.
They undergo enzymatic degradation (ex: AcHesterase).
They are then reuptaken into neuron either directly by cell or indirectly by glial cells.
There are specific transporters for uptake of neurotransmitters. What are the 2 main types of transporters?
Glutamate tranporter: uses Na+/K+ exchange and no Cl- dependence.
Other neurotransmitter transporter: uses Na+ and Cl- cotransport.
Once a neurotransmitter is transported back into the presynaptic neuron it needs to be put back into vesicles to be reused. How is this done? (super brief).
Transporter molecules get neurotransmitters into synaptic vesicles from cytoplasm.
2 for monoamines (dopamine, NE, etc.).
1 for GABA.
1 for Acetylcholine.
Regarding this reuptake of neurotransmitters. What gradients are used for reuptake into presynaptic terminal vs. vesicles?
Presynaptic terminal transporters use Na+ gradient.
Vesicle transporters use H+ gradient.
Tell me the cycle (substrates, enzymes, products) of AcH degradation and synthesis?
Acetylcholine (in synaptic cleft), broken down by AcHesterase -> Choline and acetate.
Choline recycled into presynaptic terminal, added to acetylCoA by choline acetyltransferase -> AcH.
