Lecture 9: Synaptic Transmission Flashcards
What are electrical synapses?
specialized ‘electrical junctions’ that allow flow of electrotonic current directly from one neuron to another
What are chemical synapses?
have no direct contact between neuron membranes – a chemical messenger bridges the gap (or cleft) between the cells
How are electrical synapses formed?
when the two opposing cell membranes both express connexin hemichannels – when aligned, these form large diameter (1nm) cross-cell pores called gap junctions
What is the function of electrical synapses?
allow rapid, bidirectional transfer of ions
What are electrical synapses large enough to transfer?
many cellular second messenger molecules, and other small(ish) molecules, including some dyes
What do chemical synapses act via?
via rapid, spatiotemporally precise exocytosis of synaptic vesicles containing neurotransmitter molecules – triggered in response to electrical activity in the presynaptic cell, and occurs very rapidly, but with high precision
Is vesicle exocytosis metabolically sustainable away from the cell body?
yes – synaptic vesicles and neurotransmitter molecules are recycled at the axon terminal so they don’t rely on transport down the axon to keep functioning
Is synaptic transmission tightly coupled to electrical activity? What does this mean?
yes – this means it is…
- rapid (very short delay)
- reliable (transmitter is typically only released when electrical activity has occurred – but there are a few exceptions)
Is chemical synaptic transmission modifiable?
yes – plasticity: many steps in the process of transmitter release (and transmitter detection) can be regulated by cellular activity
What is the presynaptic compartment?
releases neurotransmitter
typically the axon terminal – compartment of the neuron which is biochemically distinct from the rest of the axon
What is a synaptic vesicle?
contain neurotransmitter to be released
recycled (reformed) in the area surrounding the active zone
What is the active zone?
specialized part of the axon terminal membrane where transmitter release occurs
What is the synaptic cleft?
extracellular space crossed by neurotransmitter
What is the postsynaptic compartment?
receives neurotransmitter
- typically located on dendrite or soma
- its specializations depend on what type of synapse it is (excitatory, inhibitory or modulatory)
What is the postsynaptic density?
specialized part of the membrane where neurotransmitter receptors are located
What molecules/proteins are required for transmitter loading? (2)
- transmitter transporters
- proton pump
What molecules/proteins are required for mobilization? (1)
synapsins
What molecules/proteins are required for docking? (1)
SNAREs
What molecules/proteins are required for priming? (1)
SNAREs
What molecules/proteins are required for fusion? (3)
- synaptotagmins
- SNAREs
- VG Ca-channels
What molecules/proteins are required for coating? (2)
- clathrin
- synaptotagmins
What molecules/proteins are required for budding? (3)
- dynamin
- clathrin
- actin
What molecules/proteins are required for uncoating? (1)
clathrin
What is a neuromuscular junction?
synapse between somatic motor neuron and muscle cell (also called muscle fibre)
What is a neuromuscular junction similar to?
quite similar to excitatory synapses in the CNS
What is the terminal bouton?
(pre-synaptic) axon terminal of muscle synapse
What is the motor end plate (MEP)?
postsynaptic density in a muscle synapse
What is end plate potential (EPP)?
excitatory postsynaptic potential in a muscle synapse
What do many synapses in vertebrate peripheral nervous system, including neuromuscular junction, use as their neurotransmitter?
acetylcholine (small organic ion)
What does synaptic transmission involve?
chemical messengers (neurotransmitters) released into extracellular space
What could affect ACh signalling?
any naturally occurring toxins and venoms
What are the pros of muscle synapses (NMJs)? (4)
- accessibility – PNS not CNS
- size – muscle fibres are large cells, suited for voltage clamp experiments
- simplicity – there is only ever one synapse per vertebrate muscle fibre
- pre-studied – ACh (neurotransmitter) was known, as were naturally occurring drugs that could enhance or block its activity
What are the cons of muscle synapses (NMJs)? (2)
- no inhibition – one excitatory synapse per fibre means only one kind of synapse can be investigated with this model system
- TRADE-OFF: contractions – unlike neurons, muscle cells MOVE when they’re excited (this is terrible for electrode recordings)
What are the steps in the life of a synaptic vesicle?
- fusion with the axon membrane
- reforming from the membrane
- filling with neurotransmitter
- storing till it is needed
What are the steps at the active zone that occur before vesicle fusion?
- docking
- priming
What is docking?
process of tethering a free synaptic vesicle to the active zone
What is priming?
process of bringing a docked vesicle very close to the active zone membrane
What is fusion?
exocytosis of the vesicle by fusion with the active zone membrane and release of its neurotransmitter into the synaptic cleft
What stages are SNARE proteins key participants in?
- docking
- priming
- fusion
Which SNARE proteins are involved in the docking, priming and fusion stages? (3)
- synaptobrevin: vesicle bound v-SNARE
- syntaxin: terminal-bound t-SNARE
- SNAP-25: terminal-bound t-SNARE
What is the key process that occurs in vesicle docking?
formation of SNARE complex
How is SNARE complex formed?
when a vesicle (carrying synaptobrevin) is brought close to an active zone which contains SNAP-25 and syntaxin – make specific, relatively stable associations with each other
What must typical EPP smoothly graded EPP in normal conditions be generated by?
many quanta occurring at the same time
What is quantal synaptic transmission due to? What is the mechanism that means these responses are quantal?
neurotransmitter being released in equal-sized packets
each quantum represents neurotransmitter somehow being released in equally sized amounts (presynaptic)
What are quanta?
equal-sized packets
What do quanta correspond to?
synaptic vesicles, which fuse with axonal membrane (exocytosis), releasing their contents into the synaptic cleft
How are neurotransmitters released?
released from presynaptic axon terminal in equal-sized packets (aka quanta)
What are some observations about the relationship between Ca and neurotransmitter release?
- Ca2+ must be present in extracellular fluid for stimulated release to occur at all
- to induce neurotransmitter release, [Ca2+]o must be present at the exact time of axonal membrane depolarization (not before or after), even though vesicle fusion happens after a delay
- [Ca2+]o has a strong effect on the number of quanta released – release is proportional to [Ca++]o^4
these observations can be explained by: voltage-gated Ca2+ channels (VGCCs)
What do voltage-gated Ca2+ channels (VGCCs) open in response to?
depolarization from the AP reaching the axon terminal
Where are voltage-gated Ca2+ channels (VGCCs) enriched?
subtype of VGCCs (known as ’N-type’) are specifically enriched in active zone membrane of axon terminals
Why is the presynaptic AP not changed/barely changed by the Ca2+ chelation?
because VGCCs (and thus calcium currents) are only found in a very restricted subcompartment of the axon terminal (the active zone)
(release Ca2+ only around active zone)
What does priming involve?
stabilization of SNARE complexes by many additional proteins
What happens once a synaptic vesicle is docked by a SNARE complex?
many other active zone and axon terminal proteins also join and bind, increasing the complex’s complexity
What functions do support (non-SNARE) proteins enable (during priming)?
(assembly of support protein complexes)
- stabilization of the association between SNAREs
- positioning the vesicle-SNARE complex near VGCCs
- reinforcement, bringing the vesicle close (but not too close) to the membrane
- sites for regulation of fusion by intracellular signal cascades (ie. kinases)
What is synaptotagmin (Syt)?
fast Ca2+ sensor that catalyzes synaptic vesicle fusion
can bind Ca2+ ions – binding causes the whole Syt protein to change its conformation (ie. fold into a different shape)
What does synaptotagmin do?
binds to calcium and its interactions with SNARE proteins catalyze fusion
- when a vesicle is docked and primed, synaptotagmin (vesicle protein) physically interacts with SNARE complex
- Ca2+ binding to synaptotagmin causes it to change shape
- movement of Syt forces v-SNARE and t-SNAREs to roll up more tightly, bringing the two membranes together – this opens a path for neurotransmitter release from the vesicle
Synaptic transmission in a chemical synapse is quantal. What does this mean?
equal-sized packets of neurotransmitter are released in response to APs in presynaptic neuron due to fusion of synaptic vesicles with axon terminal membrane
Synaptic release cannot occur without what?
calcium
critical link between terminal depolarization and vesicle fusion is influx of calcium through voltage-gated calcium channels in axon terminal
