Vesicular Neurotransmitter Release
Transporters ensure that signalling occurs at discrete dendrites, but spatial (specific
regions) and temporal (fast time scale) control over signalling is necessary for NS
function. Molecular mechanisms ensure this.
Neuronal chemical axo-dendritic communication
Neurotransmitter release is a highly specialised form of membrane fusion
between vesicles and plasma membranes, controlled by molecular mechanisms
Very high spatial and temporal resolution (precision with respect to space and
time) – this spatial control is partly regulated by the location of calcium ion channels,
leading to local increases in Ca2+ and regional control of membrane vesicular fusion
events
Involves the release of small packets or quanta of transmitter – for every action
potential and membrane fusion event, a defined amount (quanta) of
neurotransmitter is released rather than random amounts of molecules released at
each synaptic transmission
Triggered by calcium-mediated fusion of vesicles – arrival of the action potential
triggers the opening of pre-synaptic calcium ion channels and Ca2+ influx, triggering
quantal release of neurotransmitter
Very rapid transduction of an electrical stimulus (action potential) into the chemical
signal of neurotransmitter vesicular release = less than 1ms
Bernard Katz & Quantal Release
The papers by Fatt & Katz (1952) and del Castillo & Katz (1954) were watershed
events in the history of synaptic physiology because they established that
neurotransmitters are released from presynaptic terminals in discrete ‘quanta’.
Bernard Katz and colleagues employed the frog neuromuscular junction, an
accessible peripheral synapse that had already been used to establish some basic
principles of synaptic action. Using the then-new technique of intracellular
microelectrode recording, Katz and colleagues recorded the postsynaptic responses
– termed the end-plate potential (EPP) – resulting from the action of acetylcholine
(ACh) on the postsynaptic muscle cell.
As described in the accompanying Classical Perspectives article by Nicholls (2007),
an earlier paper by Fatt & Katz (1951) provided the first direct measurements of the
EPP and divined some of its underlying mechanisms. Their insights into postsynaptic
mechanisms then permitted Katz and colleagues to use EPPs as a sensitive monitor
of ACh release from the presynaptic motor neuron, opening the door to dramatic
advances in our understanding of neurotransmitter release. The first big advance
came when Fatt & Katz (1952) described small, spontaneous depolarizations of the
postsynaptic membrane potential that occurred even when even the motor neuron
was not stimulated (Fig. 1, top). Because of the numerous similarities between these
events and the EPPs evoked by presynaptic stimulation (Fig. 1, bottom) – such as
waveform, spatial localization, and drug sensitivity –Fatt & Katz (1952) named these
events ‘miniature end-plate potentials’ (usually referred to as ‘minis’ in modern
parlance). Fatt & Katz (1952) reached the fundamental conclusion that minis result
from the spontaneous release of ACh from the presynaptic motor neuron. Their
experiments also established many important properties of spontaneous transmitter
release; for example, the observation that mini frequency is extremely sensitive to
, osmotic pressure has led to today's widespread use of hypertonic solutions as a
chemical means of triggering transmitter release (e.g. Rosenmund & Stevens, 1996).
Neuronal specialisation: vesicular transmitter release
2 types of vesicular neurotransmitter release:
1. Small Synaptic Vesicles
(SSVs): vesicles responsible for
release of small molecule
transmitters. Vesicles are
synthesised in the trans-golgi
network of the cell soma and are
transported to the nerve terminal
in an empty state, lacking
neurotransmitter. Synaptic vesicle
components are initially trafficked
to the synapse using members of
the kinesin motor family. In C.
elegans the major motor for
synaptic vesicles is UNC-104. Transmitters are then synthesisted and
packaged into the vesicle AT the nerve terminal. Remember, SMTs require
synthetic enzymes to be present at the nerve terminal. SSVs have the
capability to recycle vesicles at presynaptic boutons: once the vesicle has
fused with the pre-synaptic plasma membrane and released its contents, it
enters an early endosome and is transported back along the axon to the cell
soma to a late endosome before being recycled and repackaged with
neurotransmitter at the nerve terminal. This is important for the temporal
control of transmission: without this recycling mechanism, the fine control and
rapid response of NT release would not be possible. The ability to refill and
recycle vesicles determines the rate of transmission and the ability of the
synapse to be restimulated, and hence is a limiting aspect of transmission. At
the nerve terminal, SSVs have a diameter of 50nm.
2. Large Dense-Core Vesicles (LDCVs): vesicles responsible for the release of
neuropeptides (large protein-
based signalling molecules).
Neuropeptides are synthesised in
the RER as large propeptide
molecules, which are then
packaged into vesicles as they are
transported through the Golgi
network, and may enter the soma
granule pool or move directly
along the axon to the nerve
terminal. Some may undergo
direct membrane fusion and
neuropeptide release, whilst
others may enter a storage pool
before fusion is stimulated via
depolarisation and calcium influx. Once neuropeptide release has occurred,
the LDVCs can be recycled, moving back to the cell soma via retrograde
transport. At the nerve terminal, LDVCs are 5 times larger than SSVs, having a
diameter of 250nm.
Transporters ensure that signalling occurs at discrete dendrites, but spatial (specific
regions) and temporal (fast time scale) control over signalling is necessary for NS
function. Molecular mechanisms ensure this.
Neuronal chemical axo-dendritic communication
Neurotransmitter release is a highly specialised form of membrane fusion
between vesicles and plasma membranes, controlled by molecular mechanisms
Very high spatial and temporal resolution (precision with respect to space and
time) – this spatial control is partly regulated by the location of calcium ion channels,
leading to local increases in Ca2+ and regional control of membrane vesicular fusion
events
Involves the release of small packets or quanta of transmitter – for every action
potential and membrane fusion event, a defined amount (quanta) of
neurotransmitter is released rather than random amounts of molecules released at
each synaptic transmission
Triggered by calcium-mediated fusion of vesicles – arrival of the action potential
triggers the opening of pre-synaptic calcium ion channels and Ca2+ influx, triggering
quantal release of neurotransmitter
Very rapid transduction of an electrical stimulus (action potential) into the chemical
signal of neurotransmitter vesicular release = less than 1ms
Bernard Katz & Quantal Release
The papers by Fatt & Katz (1952) and del Castillo & Katz (1954) were watershed
events in the history of synaptic physiology because they established that
neurotransmitters are released from presynaptic terminals in discrete ‘quanta’.
Bernard Katz and colleagues employed the frog neuromuscular junction, an
accessible peripheral synapse that had already been used to establish some basic
principles of synaptic action. Using the then-new technique of intracellular
microelectrode recording, Katz and colleagues recorded the postsynaptic responses
– termed the end-plate potential (EPP) – resulting from the action of acetylcholine
(ACh) on the postsynaptic muscle cell.
As described in the accompanying Classical Perspectives article by Nicholls (2007),
an earlier paper by Fatt & Katz (1951) provided the first direct measurements of the
EPP and divined some of its underlying mechanisms. Their insights into postsynaptic
mechanisms then permitted Katz and colleagues to use EPPs as a sensitive monitor
of ACh release from the presynaptic motor neuron, opening the door to dramatic
advances in our understanding of neurotransmitter release. The first big advance
came when Fatt & Katz (1952) described small, spontaneous depolarizations of the
postsynaptic membrane potential that occurred even when even the motor neuron
was not stimulated (Fig. 1, top). Because of the numerous similarities between these
events and the EPPs evoked by presynaptic stimulation (Fig. 1, bottom) – such as
waveform, spatial localization, and drug sensitivity –Fatt & Katz (1952) named these
events ‘miniature end-plate potentials’ (usually referred to as ‘minis’ in modern
parlance). Fatt & Katz (1952) reached the fundamental conclusion that minis result
from the spontaneous release of ACh from the presynaptic motor neuron. Their
experiments also established many important properties of spontaneous transmitter
release; for example, the observation that mini frequency is extremely sensitive to
, osmotic pressure has led to today's widespread use of hypertonic solutions as a
chemical means of triggering transmitter release (e.g. Rosenmund & Stevens, 1996).
Neuronal specialisation: vesicular transmitter release
2 types of vesicular neurotransmitter release:
1. Small Synaptic Vesicles
(SSVs): vesicles responsible for
release of small molecule
transmitters. Vesicles are
synthesised in the trans-golgi
network of the cell soma and are
transported to the nerve terminal
in an empty state, lacking
neurotransmitter. Synaptic vesicle
components are initially trafficked
to the synapse using members of
the kinesin motor family. In C.
elegans the major motor for
synaptic vesicles is UNC-104. Transmitters are then synthesisted and
packaged into the vesicle AT the nerve terminal. Remember, SMTs require
synthetic enzymes to be present at the nerve terminal. SSVs have the
capability to recycle vesicles at presynaptic boutons: once the vesicle has
fused with the pre-synaptic plasma membrane and released its contents, it
enters an early endosome and is transported back along the axon to the cell
soma to a late endosome before being recycled and repackaged with
neurotransmitter at the nerve terminal. This is important for the temporal
control of transmission: without this recycling mechanism, the fine control and
rapid response of NT release would not be possible. The ability to refill and
recycle vesicles determines the rate of transmission and the ability of the
synapse to be restimulated, and hence is a limiting aspect of transmission. At
the nerve terminal, SSVs have a diameter of 50nm.
2. Large Dense-Core Vesicles (LDCVs): vesicles responsible for the release of
neuropeptides (large protein-
based signalling molecules).
Neuropeptides are synthesised in
the RER as large propeptide
molecules, which are then
packaged into vesicles as they are
transported through the Golgi
network, and may enter the soma
granule pool or move directly
along the axon to the nerve
terminal. Some may undergo
direct membrane fusion and
neuropeptide release, whilst
others may enter a storage pool
before fusion is stimulated via
depolarisation and calcium influx. Once neuropeptide release has occurred,
the LDVCs can be recycled, moving back to the cell soma via retrograde
transport. At the nerve terminal, LDVCs are 5 times larger than SSVs, having a
diameter of 250nm.
