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Neuro > Lecture 10: Neurotransmitter Release > Flashcards

Lecture 10: Neurotransmitter Release Flashcards

1
Q

Storage and release of synaptic vesicles: 2

A
  1. Active zone = release site vesicles
  2. High density vesicles/high density Ca2+ channels
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2
Q

UNDERSTANDING Storage and release of synaptic vesicles = WHAT ARE ACTIVE SITES

A
  1. Active Zone: specialized region of the presynaptic terminal where neurotransmitter release occurs.

Characteristics:
2.’High Density of Vesicles:’ Many synaptic vesicles are clustered in this area, ready to release their contents.

3.’High Density of Ca²⁺ Channels:’ There are many voltage-gated calcium channels concentrated in the active zone

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3
Q

UNDERSTANDING Storage and release of synaptic vesicles = WHERE ARE VESICLES STORED?

A
  1. Location: stored in the presynaptic terminal, particularly near the active zone.
  2. Organisation: Vesicles are organised in clusters or “pools” close to the release sites.
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4
Q

Vesicle Release Mechanism

A
  1. Action Potential Arrival
  2. Calcium Influx
  3. Vesicle Fusion
  4. Neurotransmitter Release
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5
Q

High-Density Features:

A
  1. High-Density Vesicles: These vesicles are typically clustered near the active zone, ready to release their contents when triggered by an influx of calcium ions.
  2. High-Density Ca²⁺ Channels:
    - These channels are located at the active zone and play a crucial role in initiating neurotransmitter release.
    - When an action potential arrives at the presynaptic terminal, these channels open, allowing Ca²⁺ ions to enter the cell.
    - The increase in intracellular calcium concentration triggers the fusion of synaptic vesicles with the presynaptic membrane, leading to neurotransmitter release
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6
Q

3 steps to Detection of transmitter release

A
  1. Measure MEMBRANE CAPACITANCE
  2. PRE-LOAD VESICLES with a FLUORESCENT DYE and IMAGE VESICULAR RELEASE
  3. Use ELECTROCHEMICAL PROBE to DETECT BREAKDOWN PRODUCTS
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7
Q

Vesicle cycle IN SIMPLE STEPS 4

A
  1. Targeting, tethering, docking
  2. Release
  3. Membrane and transmitter recovery/breakdown
  4. Vesicle replenishing and recycling
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8
Q

Vesicle Cycle in detail

A
  1. ‘Vesicle Docking’: Synaptic vesicles dock at the active zone of the presynaptic membrane.
  2. ‘Priming’: Vesicles are primed, making them ready for rapid release upon stimulation.
  3. ‘Calcium Influx:’ An action potential triggers the opening of Ca²⁺ channels, allowing calcium to enter the presynaptic terminal.
  4. ‘Vesicle Fusion:’ The influx of Ca²⁺ leads to the fusion of vesicles with the presynaptic membrane, releasing neurotransmitters into the synaptic cleft.
  5. ‘Neurotransmitter Release’: Neurotransmitters are released and bind to receptors on the postsynaptic membrane.

6.’Endocytosis’: After release, the vesicle membrane is retrieved via endocytosis.

  1. ‘Recycling’: Retrieved vesicles are refilled with neurotransmitters and either stored for future release or immediately re-enter the cycle.
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9
Q

What are the TWO POPULATIONS OF VESICLES?

A
  1. Storage pool or Reserve pool (RP)
  2. Readily releasable pool (RRP)
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10
Q

Characteristics of storage pool or reserve pool (RP)? 2

A
  1. Only recruited at HIGHER FREQUENCIES of nerve
    stimulation
  2. Bound to microtubules (ACTIN) by SYNAPSIN I
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11
Q

Characteristics of Readily Releasable Pool (RRP)? 2

A
  1. Ready for immediate release, located near the active zone.
  2. Defines release probability (p).
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12
Q

Reserve Pool to Readily Releasable Pool (Doussau and Augustine, Biochimie, 2000): 3

A
  1. ‘Ca²⁺ Activation:’
    - Calcium activates a protein kinase.
  2. ‘Synapsin Phosphorylation:’
    - The activated kinase phosphorylates synapsin.
  3. ‘Vesicle Migration:’
    - Phosphorylated synapsin allows vesicles from the reserve pool to migrate to the active zone,
    - replenishing the readily releasable pool (RRP).
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13
Q

Calcium Influx Induces Release: 2

A
  1. Calcium influx can be immediately effective because only local concentration needs to rise (nanodomain/microdomain).
  2. Concentration reaches approximately 100 µM and dissipates quickly.
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14
Q

Calcium influx induces release… THREE TYPES

A
  1. NANODOMAIN
    - synaptic variant
    - CBP to plasma membrane
    - CALCIUM CHANNEL
  2. MICRODOMAIN
    -synaptic membrane
    MULTIPLE CALCIUM CHANNELS
  3. RADIAL GRADIENT
    - synaptic vesicles, to plasma membrane
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15
Q

Vesicle Tethering, Docking, and Priming …define each

A
  1. Tethering: Initial attachment of the vesicle to the presynaptic membrane.
  2. Docking: Vesicle is positioned at the active zone, close to the release site.
  3. Priming: Prepares the vesicle for rapid fusion upon calcium influx.
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16
Q

Vesicle Tethering, Docking, and Priming …UNDERSTANDING ‘SNARE COMPLEX’

  • The types?
A
  1. ‘SNARE Complex:’
    - Critical for vesicle fusion, composed of V-SNARE and T-SNARE proteins.
  2. ‘V-SNARE:’ Includes synaptobrevin (also called VAMP) on the vesicle membrane.
  3. ‘T-SNARE:’ Includes syntaxin on the target (presynaptic) membrane.
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17
Q

Vesicle tethering, docking, priming involves

A

Involvement of many different proteins

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18
Q

Vesicle Tethering, Docking, and Priming: Involvement of Multiple Proteins

A

Tethering:
1. Vesicle-associated membrane protein (VAMP).
2. SNAP-25.
3. Syntaxin.

“Complexin”: Stabilizes the SNARE complex during vesicle tethering.

Docking:
1. Vesicle.
2. Synaptotagmin: Acts as a calcium sensor.
3. Calcium (Ca²⁺) binding sites: Crucial for triggering vesicle fusion.

Priming:
1. Rapid complete membrane fusion.
2. α-SNAP: Assists in SNARE complex disassembly.
3. NSF (N-ethylmaleimide-sensitive factor): Unwinds the SNARE complex.
4. ATP → ADP + P: Energy-dependent process.
5. n-sec1: Also known as Munc18, regulates SNARE complex formation.

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19
Q

understanding ‘Calcium-Triggered Release via Synaptotagmin:’ 3

A
  1. ‘Ca²⁺ Binding:’ Calcium binds to the C2A domain of synaptotagmin.
  2. ‘C2B Domain:’ Required for maximal association with syntaxin.
  3. ‘Impact of Mutations:’ Neurotransmitter release is reduced by mutations that PREVENT SYNAPTOTAGMIN (and other proteins) from binding to SYNTAXIN.
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20
Q

Synaptobrevin:

A

A V-SNARE protein involved in vesicle fusion.

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21
Q

Synaptophysin:

A

A vesicle membrane protein that interacts with synaptobrevin.

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22
Q

Syntaxin:

A

A T-SNARE protein on the presynaptic membrane, crucial for docking and fusion.

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23
Q

nSec1 (Munc18):

A

Regulates the assembly of the SNARE complex and interacts with syntaxin.

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24
Q

SNAP-25:

A

A T-SNARE protein that forms part of the SNARE complex, facilitating vesicle fusion.

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25
Q

Synaptotagmin:

A

Acts as a calcium sensor, binding Ca²⁺ and interacting with the SNARE complex to trigger fusion

26
Q

Rab3A:

A

A small GTPase involved in vesicle trafficking and docking.

27
Q

Rabphilin-3A:

A

An effector protein of Rab3A, involved in vesicle docking and release regulation.

28
Q

NSF (N-ethylmaleimide-sensitive factor):

A

Involved in the disassembly of the SNARE complex post-fusion.

29
Q

α-SNAP:

A

Assists NSF in disassembling the SNARE complex to recycle SNARE proteins.

30
Q

Botulinum Toxin (Botox) and its Neuroscience Context:

A
  1. ‘Botulinum Toxin’: A neurotoxin produced by the bacterium Clostridium botulinum.
  2. It prevents the release of acetylcholine (ACh) at the neuromuscular junction.
  3. Mechanism: Botulinum toxin cleaves SNARE proteins, which are essential for vesicle fusion and neurotransmitter release.
31
Q

Botulinum Toxin (Botox) and its Neuroscience Context: REGULAR VS EXPOSURE

A
  1. Regular Synaptic Transmission:
    - Involves intact SNARE proteins (e.g., synaptobrevin, syntaxin, SNAP-25) that facilitate the release of neurotransmitters like ACh.
  2. Exposure to Botox:
    - Cleavage of SNARE proteins by botulinum toxin disrupts this process, inhibiting neurotransmitter release and leading to muscle paralysis or reduced muscle activity.
32
Q

Normal Neurotransmitter Release 9.

A
  1. at NMJ - motor nerve terminus in muscle cell
  2. SNARE PROTEINS
    - Synaptobrevin
    - SNAP-25
    - Syntaxin
  3. Synaptic Vesicle
  4. SNARE protein Form complex
  5. synaptic fusion complex
  6. VESICLE AND TERMINAL MEMBRANES FUSE
  7. NEUROTRANSMITTER RELEASED
  8. Acetylcholine to Ach receptor
  9. MUSCLE FIBER CONTRACTS
33
Q

EXPOSURE TO BOTULINUM TOXIN

A
  1. in muscle cell ‘Botulinum Toxin’
  2. Botulinum Toxin Endocytosed
  3. heavy chain and light chain
  4. LIGHT CHAIN CLEAVES SPECIFIC ‘SNARE’ PROTEINS
    - TYPE C = neurotransmitter not released …MUSCLE FIBRE PARALYSED
    - TYPE A, C, E = membranes Do not fuse
    - TYPE B, D, F, G = ‘SNARE’ Complex Does not form
34
Q

Membrane Fusion Process: 6

A
  1. ‘SNARE Complex:’ Composed of V-SNARE (e.g., synaptobrevin), T-SNARE (e.g., syntaxin, SNAP-25), and helps facilitate vesicle fusion.

2.’Synaptotagmin’: Binds calcium ions, which triggers the final steps of membrane fusion.

  1. Mechanism:

…4. The SNARE complex “pulls” the vesicle and target membranes together.

…5. This action forces the membranes to merge, forming a fusion pore.

…6.The fusion pore allows neurotransmitters to be released into the synaptic cleft.

35
Q

Trans-SNARE Complexes and Membrane Fusion:

A

Trans-SNARE Complexes:
– Formed between V-SNAREs (vesicle membrane) and T-SNAREs (target membrane).

“Exert Inward Force (F):”
– This FORCE PULLS the VESICLE and TARGET MEMBRANE TOGETHER facilitating membrane fusion

36
Q

cis-SNARE Complexes and Membrane Fusion: 3

A
  1. “Formed after fusion”, where the SNARE complexes are on a SINGLE, FUSED MEMBRANE.
  2. ‘No Force’: The cis-SNARE complexes do not exert additional force for fusion; they stabilize the fused membrane.
  3. ‘Single, Fused Membrane:’ The RESULT OF MEMBRANE FUSION, containing a FUSION PORE through which neurotransmitters are RELEASED.
37
Q

Stages of Membrane Fusion: 6

A

1.’Initial Contact’:
- The vesicle and target membranes come into close proximity, facilitated by the SNARE complex.

  1. ‘Contact Between Protein-Depleted Bilayer Patches’:
    • The membranes contact each other at areas where proteins have been removed or are less concentrated, creating localized points of interaction.
  2. ‘Hemifusion Stalk’:
    • Formation of a stalk-like structure where the outer leaflets of the vesicle and target membranes merge, while the inner leaflets remain separate.
  3. ‘Hemifusion Diaphragm’:
    • The hemifusion stalk expands into a diaphragm-like structure, where the outer leaflets are fully fused but the inner leaflets have not yet merged.
  4. ‘Post-Fusion Conformation’:
    • The membranes fully merge, leading to a single continuous membrane structure with the SNARE complexes in a post-fusion state.
  5. ‘Initial Fusion Pore’:
    • The formation of a small, initial fusion pore that allows the release of neurotransmitters from the vesicle into the synaptic cleft.
38
Q

Membrane fusion

A

neurotransmitter release machinery

39
Q

Membrane Fusion and Neurotransmitter Release Machinery (Südhof, Neuron 2013):

A
  1. SNARE Complex: Central to membrane fusion, composed of V-SNAREs (e.g., synaptobrevin), T-SNAREs (e.g., syntaxin, SNAP-25), which pull the vesicle and target membranes together.
  2. Synaptotagmin: Binds calcium ions and triggers the final stages of fusion.
  3. Rab GTPases: (e.g., Rab3A) Involved in vesicle docking and regulation.
  4. Complexin: Stabilizes the SNARE complex and regulates the transition to full fusion.
  5. NSF and α-SNAP: Facilitate the disassembly and recycling of the SNARE complex after fusion.
  6. Calcium Channels: Ensure precise timing by allowing Ca²⁺ influx, which is crucial for triggering the fusion process.
40
Q

Membrane Fusion:

SNAREs Alone: 3

A
  1. Formation of SNARE Complex: V-SNAREs (e.g., synaptobrevin) and T-SNAREs (e.g., syntaxin, SNAP-25) form a complex.
  2. Docking of Synaptic Vesicle: The complex pulls the vesicle and target membranes together.
  3. Membrane Fusion: Fusion of the vesicle and target membranes, forming a fusion pore.
41
Q

membrane fusion SNAREs and Munc18-1: 6

A
  1. Complex Formation: Munc18-1 (nSec1) binds to syntaxin, stabilizing the SNARE complex formation.
  2. SNAP-25 and Munc13:

…3.SNAP-25 interacts with syntaxin and synaptobrevin.

…4. Munc13 facilitates the priming of the SNARE complex.

  1. Docking and Priming: The vesicle is primed for fusion with the target membrane.
  2. Fusion and Release: Calcium binding to synaptotagmin triggers the final fusion, leading to neurotransmitter release.
42
Q

Membrane fusion OVERVIEW

A

ON SLIDE 17

43
Q

Vesicle Recycling: why?

A
  1. ‘Fusion and Surface Area:’ Fusion of vesicles with the plasma membrane INCREASES the SURFACE AREA of the nerve terminal.
  2. ‘Capacitance Increase’: The increase in surface area results in a HIGHER MEMBRANE CAPACITANCE, WHICH CAN BE MEASURED.

3.’Monitoring Recycling:’ Vesicle recycling can be MONITORED BY A DECREASE IN CAPACITANCE, as the membrane surface area RETURNS TO NORMAL AFTER VESICLE RETRIEVAL AND RECYCLING.

44
Q

Vesicle Recycling: 10 STEPS

A
  1. ‘Clathrin Coat Formation’:

…2.Clathrin molecules assemble into a coat around the vesicle, forming a structure from multiple clathrin triskelia.
…3. This coat aids in budding the vesicle from the plasma membrane.

4.’Vesicle Budding’:

…5.The clathrin-coated vesicle buds off from the plasma membrane.

6.’Uncoating’:

…7.After budding, the clathrin coat is removed from the vesicle.
…8. Molecular chaperones Hsc-70 and auxilin facilitate the uncoating process.

9.’Recycling’:
…10. The uncoated vesicle is recycled and refilled with neurotransmitters for future use.

44
Q

Vesicle Recycling (Purves et al., Neuroscience, 2012, Fig. 5.15):

4

A

1.’Clathrin Coat:’ During vesicle recycling, clathrin forms a coat around the vesicle from multiple clathrin triskelia.

  1. This coat helps in budding the vesicle from the plasma membrane.
  2. Uncoating: After the vesicle has budded off, the clathrin coat is removed by the molecular chaperones Hsc-70 and auxilin,
  3. allowing the vesicle to be recycled and refilled with neurotransmitters.
45
Q

Single-Vesicle Exo-Endocytosis:

Kiss-and-Run: 3

A
  1. ‘Fusion:’ The vesicle docks at the plasma membrane and fuses partially.
  2. ‘Release:’
    Neurotransmitters are released through a small fusion pore.
  3. ‘Resealing:’ The vesicle quickly detaches from the membrane and reseals, maintaining its shape
46
Q

Single-Vesicle Exo-Endocytosis:

‘Full Fusion and Reformation:’ 4

A
  1. ‘Fusion:’
    The vesicle fully merges with the plasma membrane, forming a large fusion pore.
  2. ‘Release:’
    Neurotransmitters are released into the synaptic cleft.
  3. ‘Endocytosis:’
    The plasma membrane is internalized, and a new vesicle is formed.
  4. ‘Refilling:’
    The new vesicle is refilled with neurotransmitters and prepared for reuse
47
Q

Single-Vesicle Exo-Endocytosis:

Clathrin-Mediated Endocytosis: 4

A
  1. ‘Fusion’:
    The vesicle fully merges with the plasma membrane.
  2. ‘Clathrin Coating:’
    Clathrin proteins form a coat around the budding vesicle.
  3. ‘Budding’:
    The clathrin-coated vesicle pinches off from the membrane.
  4. ‘Uncoating’:
    The clathrin coat is removed, and the vesicle is recycled and refilled with neurotransmitters.
48
Q

ynaptic Specialization: Ribbon Synapse (Cochlear Hair Cells)

A
  1. ‘Ribbon Structure:’ The ribbon serves to TETHER MULTIPLE VESICLES at the presynaptic terminal,
  2. KEEPING THEM READY FOR RELEASE
  3. ‘High-Speed Synapses:’ This specialized structure supports HIGH-SPEED SYNAPIC TRANSMISSION
  4. essential for ENCODING RAPID AUDITORY SIGNALS
49
Q

Multiquantal Release: 3

A
  1. The simultaneous release of multiple quanta (packets) of neurotransmitter.
  2. Function: The RIBBON’S ABILITY to KEEP MULTIPLE VESICLES READY ALLOWS FOR “MULTIQUANTAL RELEASE”,
  3. providing a LARGE and SUSTAINED SYNAPTIC RESPONSE NECESSARY FOR HIGH FREQUENCY SIGNALING
50
Q

Ribbon synapses in cochlear hair cell allow for
multiple neural outputs with different thresholds

LOW THRESHOLD

A
  1. ‘Calcium Channels’: These ribbons may have a greater number of calcium channels.
  2. ‘Release Frequency’: They release neurotransmitters more frequently at a given membrane potential.
  3. ‘Afferent Action Potentials’:
    - This leads to more frequent firing of afferent action potentials,
    - allowing for more sensitive detection of sound.
51
Q

Ribbon synapses in cochlear hair cell allow for
multiple neural outputs with different thresholds

HIGH THRESHOLD

A
  1. ‘Calcium Channels’:
    - These ribbons have fewer calcium channels.
  2. ‘Depolarization Requirement’:
    - They require greater depolarization to achieve the same level of neurotransmitter release.
  3. ‘Afferent Activity’:
    - As a result, they trigger fewer afferent action potentials at lower levels of depolarization,
    - making them less sensitive to sound.
52
Q

Ribbon synapses in cochlear hair cell allow for
multiple neural outputs with different thresholds

LOW VS HIGH THRESHOLD

A

The difference in calcium channel density and release frequency between low and high threshold ribbons allows cochlear hair cells to encode a range of auditory stimuli with varying sensitivities.

53
Q

Alternatively, variations in vesicular fusion could
produce similar outcomes = 4

A

MODES OF SYNAPTIC VESICLE FUSION AT RIBBON SYNAPSES

  1. PROGRESSIVE FUSION
  2. SEQUENTIAL FUSION
  3. HOMOTYPIC FUSION
  4. SYNCHRONISED FUSION
54
Q

Sequential Fusion

A

Description: Vesicles fuse in a specific order, often driven by the state of the synaptic ribbon and calcium levels.

Outcome: Results in controlled release of neurotransmitters, modulating timing and quantity of signal transmission.

55
Q

Progressive Fusion:

A

Description: Vesicles fuse progressively, one after another, in sequence.

Outcome: Allows for a gradual increase in neurotransmitter release, contributing to a sustained synaptic output.

56
Q

Homotypic Fusion

A

Description: Vesicles of the same type fuse with each other, often within the same synaptic terminal.

Outcome: Aids in recycling and replenishing vesicles with consistent properties and neurotransmitter content.

57
Q

Synchronized Fusion

A

Description: Multiple vesicles fuse simultaneously or in close succession, triggered by a coordinated calcium influx.

Outcome: Produces a large, rapid release of neurotransmitters, crucial for high-speed synaptic responses.

58
Q

Size and Structure of Synaptic Boutons:

CNS Synapses

A

Synaptic boutons are much smaller compared to neuromuscular junctions.

They often contain only one or a few active zones, which are the sites where neurotransmitter release occurs.

59
Q

Mechanism of Transmitter Release:

CNS Synapses: 4

A
  1. The mechanism of neurotransmitter release can vary between different synapses and even at the same synapse.
  2. Complete Exocytosis: Vesicles fully fuse with the membrane to release neurotransmitters.
  3. Kiss-and-Run Release: Vesicles partially fuse with the membrane and release neurotransmitters through a transitory fusion pore, then quickly reseal.
  4. These variations can cause differences in quantal size (the amount of neurotransmitter released per vesicle) and vesicle diamete1.
60
Q

Multiquantal Release:

CNS Synapses:

A

The ability to release multiple quanta of neurotransmitter simultaneously (multiquantal release) is a feature that enhances the efficiency and flexibility of synaptic signaling.

This allows for a more robust and adaptable response to neural activity.

These differences highlight how neurotransmission in the CNS is specialized to meet the unique demands of neural circuits and signaling compared to the more straightforward neuromuscular junctions.

Neuro (6 decks)

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