SUBSCRIBE

what-when-how
In Depth Tutorials and Information

Neurotransmitters (The Neuron) Part 1

Chemical transmission is the major mechanism of synaptic communication in the brain. To
understand how neurotransmitters function, several issues must be addressed. These issues
include how neurotransmitters are synthesized, released, removed from the synaptic cleft, and
metabolized. In addition, it is important to identify the characteristics, anatomical loci, and
functional properties of the receptors that mediate the actions of these transmitters. Moreover,
wherever possible, the role of these transmitters in the central nervous system (CNS) functions
and their linkage to clinical disorders need to be considered.

Definition
A neurotransmitter is defined as a chemical substance that is synthesized in a neuron, released at
a synapse following depolarization of the nerve terminal (usually dependent on influx of calcium
ions), which binds to receptors on the postsynaptic cell and/or presynaptic terminal to elicit a
specific response.

Criteria Used For Identifying Neurotransmitters

The criteria for accepting a substance as a transmitter include: (1) the substance must be
synthesized in the neuron, and the enzymes needed for its synthesis must be present in the
neuron; (2) it must be released in sufficient quantity to elicit a response from the postsyn-aptic
neuron or cell located in the effector organ; (3) mechanisms for removal or inactivation of the
neurotransmitter from the synaptic cleft must exist; and (4) it should mimic the action of the
endogenously released neurotransmitter when administered exoge-nously at or near a synapse.

Major Classes of Neurotransmitters

Neurotransmitters in the nervous system can be classified into the following major categories:
small molecule transmitters, neuroactive peptides, and gaseous neurotransmit-ters (Table 8-1).

Mechanism of Transmitter Release

An action potential depolarizes the presynaptic nerve terminal, voltage-gated Ca2+ (calcium)
channels located in the presynaptic terminal membrane open, Ca2+ permeability increases, and
Ca2+ enters the terminal.These events cause the membrane of the vesicles to fuse with the
presynaptic membrane at the active zone and release the neurotransmitter into the synaptic cleft
(Fig. 8-1B). This process of transmitter release is called exocytosis (see the following section). The
neurotrans-mitter then diffuses across the synaptic cleft to the membrane of the postsynaptic

neuron, interacts with its specific receptors, and opens or closes several thousand channels in the
postsynaptic membrane, through which specific ions enter or leave the neuron (i.e., the
permeability of different ion species is changed [Fig. 8-1C]).
The nature of the response (i.e., excitatory or inhibitory) elicited at the postsynaptic neuron does
not depend on the chemical nature of the transmitter. Instead, it depends on the type of receptor
being activated and the ion species that becomes more permeable. For example, acetylcholine
(Ach) produces synaptic excitation at the neuromuscular junction (skeletal muscle contraction) by
binding with the cholinergic nicotinic receptor, whereas the same transmitter produces an inhibitory
response (decrease in heart rate) by interacting with a cholinergic muscarinic receptor located in
the cardiac tissue. As stated earlier, chemical synapses are much more common than electrical
synapses in the nervous system. They are involved in mediating complex functions. One of the
important characteristics of chemical synapses is that they can amplify signals (i.e., a small
presynaptic nerve terminal can change the potential of a large postsynaptic cell).
TABLE 8-1 Major Classes of Neurotransmitters
SmallMoleculeNeurotransmitters

Neuropeptides

GaseousNeurotransmitters

Acetylcholine

Opioidpeptides

Nitricoxide

Excitatoryaminoacids

bendorphin,

Glutamate

Methionineenkephalin

Aspartate

Leucineenkephalin

Inhibitoryaminoacids

Endomorphins

GABA

Nociceptin

Glycine

Biogenicamines
Catecholamines
Dopamine
Norepinephrine
Epinephrine
Indoleamine
Serotonin(5hydroxytryptamine,[5HT])

SubstanceP

Imidazoleamine
Histamine
Purines
ATP
Adenosine

ATP = adenosine triphosphate; GABA = gamma aminobutyric acid.

Exocytosis
The process by which a neurotransmitter contained in vesicles is released into the synaptic
cleft is called exocytosis. This process is complex and incompletely understood. The events
leading to exocytosis can be summarized as follows. The vesicular membrane contains a SNARE
protein ("SNARE" stands for "SNAP Receptors," "SNAP" stands for "Soluble NSF Attachment
Protein," and "NSF" stands for "N-ethylmaleimide Sensitive Fusion Protein"), synaptobrevin, and a
calcium-binding protein, synaptotagmin.The presynaptic membrane contains other SNARE
proteins, syntaxin, and SNAP-25 (Fig. 8-2A). The SNARE proteins in the vesicular and presynaptic
membranes interact to form complexes, and this interaction results in close apposition of the
vesicular and the presynaptic membranes (Fig. 8-2B). Depolarization of the presynap-tic terminal
membrane by an action potential results in the influx of Ca2+ ions into the terminal through
voltage-gated Ca2+ channels.Calcium ions interact with synaptotagmin, and this interaction
promotes fusion of the vesicular and presynaptic membranes (Fig. 8-2C). An opening develops in
the fused membrane and the contents of the vesicle are released into the synaptic cleft (Fig. 82D). The neurotransmitter released into the synaptic cleft binds with specific receptors, and a
response is elicited. The released transmitter enters back into the terminal by an uptake
mechanism and is recycled for subsequent release. Some neurotransmitters (e.g., Ach) are
degraded in the synaptic cleft, and one or more of their degradation products are taken back into
the terminal and reused to synthesize the neuro-transmitter in the terminal.

Recycling of Synaptic Vesicle Membranes

Initial formation of vesicles takes place in the endoplasmic reticulum and Golgi apparatus
located in the neuronal cell body. The vesicles are transported to the terminal by axonal transport.
During exocytosis the vesicular and pre-synaptic terminal membranes fuse. Thus, new membrane
is added to the presynpatic terminal membrane. The fused vesicular membrane is retrieved and
recycled within a minute by a complex process called endocytotic budding. The process can be
summarized as follows. Several proteins, including clathrin, form a basket-like lattice on the
remnants of the fused vesicle giving the appearance of a coated pit (Fig. 8-3A), which is then
pinched off from the presynaptic membrane by another protein called dynamin (Fig. 8-3B) and the
coated vesicle moves into the cytoplasm (Fig. 8-3C). The coating is removed from the vesicle by a

number of ATPases (Fig. 8-3D). Another protein, synapsin, brings about tethering of the newly
formed uncoated vesicle to the cytoskeleton (Fig. 8-3E). When mobilization of the vesicles is
needed, protein kinases phosphorylate synapsin causing it to dissociate from the vesicle, which
contains the appropriate neurotransmitter and is ready to undergo the process of exocytosis (Fig.
8-3F). Thus, during continuous neuronal activity, the retrieved vesicular membrane is recycled in
the terminal to form new synaptic vesicles and contains the neurotrans-mitter that is then released.
In this manner, rapid replacement of synaptic vesicles during continuous neuronal activity
becomes possible because synaptic vesicles form in the terminal. The synaptic vesicles produced
in the neuro-nal cell body would not be readily available due to the long distance between the
neuronal cell body and the terminal. Some of the vesicular membrane retrieved from the
cytoplasm of the nerve terminal is transported back into the cell body and is either degraded or
recycled.

FIGURE 8-2 Steps involved in exocytosis. (A) SNARE (SNAP receptor) proteins on the
vesicle and the presynaptic plasma membrane. (B) SNARE proteins on the vesicle and the
presynaptic plasma membrane form complexes. (C) Formation of SNARE protein
complexes pulls the vesicle closer to the presynaptic plasma membrane and Ca2+
(calcium) entering into the terminal via the voltage-gated Ca2+ channels binds with
synaptotagmin. (D) Binding of Ca2+ to synaptotagmin promotes fusion of the vesicle to the
presynaptic plasma membrane.

FIGURE 8-3 Recycling of synaptic vesicle membrane. (A) Clathrin, a protein, coats the
remnants of the vesicular membrane. (B) Dynamin, another protein, pinches off the coated
vesicular membrane. (C) The coated vesicular membrane is now carried into the cytoplasm
of the presynaptic terminal. (D) An ATPase removes the coating from the vesicle. (E)
Synapsin, another protein, binds to the vesicle and attaches it to the actin filaments in the
cytoskeleton. (F) A protein kinase phosphorylates synapsin, which then dissociates from
the vesicle. The vesicle then undergoes further processing before it can participate in
exocytosis.

Steps Involved in Neurotransmitter Release

Small Molecule Neurotransmitters
The following steps are involved in the synthesis, transport, and release of small molecule
neurotransmitters (Fig. 8-4A).
1. The enzymes required for synthesis of small molecule transmitters are synthesized in the
neuronal cell body in the rough endoplasmic reticulum.
2. They are transported to the Golgi apparatus.
3. In the Golgi apparatus, they are modified (e.g., sulfation, glycosylation).
4. Soluble enzymes (e.g., acetylcholinesterase, tyrosine hydroxylase) are transported along the
axon to the nerve terminal by slow anterograde axonal transport (0.5-5 mm/day) via microtubules.
The remaining enzymes are transported by fast anterograde axonal transport.
5. The precursor needed for the synthesis of small molecule neurotransmitters is taken up via
transporter proteins located in the plasma membrane of the nerve terminal, and the
neurotransmitter is synthesized in the presynaptic nerve terminal from the precursor. The enzyme
needed for the synthesis of the neurotransmit-ter is synthesized in the neuronal cell body and
transported to the terminal.
6. The synthesized pool of the neurotransmitter in the cytoplasm is taken up into small vesicles
by vesicular membrane transport proteins. Small-molecule transmitters are usually contained in
clear-core vesicles. Serotonin and norepinephrine are exceptions because they are contained in
dense-core vesicles.
7. The appropriate stimulus results in the release of the neurotransmitter by exocytosis.

Neuropeptide Neurotransmitters
These neurotransmitters usually mediate slow, ongoing brain functions. Only a few important
peptides (e.g., substance P and enkephalins) will be discussed in this topic. The following steps
are involved in the synthesis, transport, and release of neuropeptide neurotrans-mitters (Fig. 84B).
1. Polypeptides much larger than the final peptide transmitter (called pre-propeptides) are
synthesized in rough endoplasmic reticulum where they are converted into a propeptide (prepropeptide from which the signal sequence of amino acids is removed). The enzymes needed for
the cleavage of polypeptides are also synthesized in the rough endoplasmic reticulum.
2. The propeptide and the enzymes are transported to the Golgi apparatus where they are
packaged into vesicles.
3. The propeptide and enzyme-filled vesicles are carried along the axon to the nerve terminal by
fast axonal transport (400 mm/day) via microtubules. Adenosine triphosphate-requiring "motor"
proteins, such as kines-ins, are needed for this transport.

FIGURE 8-4 Steps involved in the synthesis, transport, and release of neurotransmitters.
(A) Small molecule neurotransmitters. (B) Neuropeptides. Ca2+ = calcium.
4. Enzymes cleave the propeptide to produce a smaller peptide transmitter that remains in the
large dense-core vesicles.
5. The peptide neurotransmitter is then released into the synaptic cleft by exocytosis.
6. After the release, the peptide transmitter diffuses away and is degraded by proteolytic
enzymes; it is not taken back into the nerve terminal as is the case with small molecule
neurotransmitters.
More than one transmitter (usually a small-molecule transmitter and a neuroactive peptide)
coexist in many mature neurons (e.g., most spinal motor neurons contain acetylcholine and
calcitonin gene-related peptide).