By
Dr Jay Shastri
Chemical Synapse
Electrical Synapse
The three main parts of a synapse, are an axon
terminal, the membrane encasing the tip of an
adjacent dendritic spine, and the minute space
separating the structures—the synaptic cleft.
On the tip of the dendritic spine is the
postsynaptic membrane.
The patch of dark material within it, consists
largely of protein molecules specialized for
receiving chemical messages.
The dark patches in the presynaptic membrane—
the membrane of the axon terminal—consist
largely of protein molecules, most of them
serving as channels and pumps and as receptor
sites.
Within the axon terminal are many other
specialized structures, including mitochondria
(the organelles that supply the cell’s energy
needs); round granules called synaptic vesicles,
which contain the chemical neurotransmitter; and
tubules that give the terminal button its shape.
In some axon terminals, larger storage granules
hold a number of synaptic vesicles.
The synapse is closely surrounded by many other
structures, including glial cells, other axons and
dendritic processes, and other synapses.
Chemical synapses predominate in the
mammalian nervous system but are not the
only kind of synapse.
Some neurons influence each other
electrically through a gap junction, or
electrical synapse, where the prejunction and
postjunction cell membranes are fused.
Ion channels in one cell membrane connect to
ion channels in the adjoining membrane,
forming a pore that allows ions to pass
directly from one neuron to the next.
This fusion eliminates the brief delay in
information flow—about 5 milliseconds per
synapse—of chemical transmission.
Gap junctions in the mammalian brain are
found in some regions, where they allow
groups of interneurons to synchronize their
firing rhythmically.
Gap junctions also allow glial cells and
neurons to exchange substances.
The possible advantages of chemical synapses
center on their plasticity. They are flexible in
controlling whether to pass a message from one
neuron to the next, they can amplify or diminish
a signal sent from one neuron to the next, and
they can change with experience to alter their
signals and therefore mediate learning.
The possible advantages of electrical synapses
are speed of impulse transmission and their
effect of binding neurons together functionally to
enhance their role in teamwork, as might be
required for some forms of memory.
Information is transmitted across a chemical synapse in
four basic steps. Each step requires a different chemical
reaction.
1. During synthesis, either the transmitter is produced by
the cell’s DNA and imported into the axon terminal or its
building blocks are imported and it is manufactured in the
axon terminal.
2. During release, the transmitter is transported to the
presynaptic membrane and released in response to an
action potential.
3. During receptor action, the transmitter traverses the
synaptic cleft and interacts with receptors on the target
cell’s membrane.
4. During inactivation, the transmitter either is drawn back
into the presynaptic axon or breaks down in the synaptic
cleft. Otherwise, it would continue to work indefinitely.
Neurotransmitters are derived in two basic ways.
Some are synthesized as proteins in the cell body
according to instructions in the neuron’s DNA.
These neurotransmitters are then packaged in
membranes on the Golgi bodies and transported
on microtubules to the axon terminal.
Messenger RNA also may be transported to the
synapse, where it directs transmitter synthesis
within the axon terminal rather than within the
ribosomes surrounding the nucleus.
Other neurotransmitters are synthesized in the
axon terminal from building blocks derived from
food.
Transporter proteins , molecules in the cell
membrane that pump substances across it,
absorb these precursor chemicals from the blood
supply.
Mitochondria in the axon terminal provide the
energy for synthesizing neurotransmitters from
their precursor chemicals.
(Sometimes the transporters absorb entire ready-
made neurotransmitters from the blood.)
These two basic modes of synthesis divide
most neurotransmitter substances into two
large classes: a quicker-acting class derived
from nutrient building blocks and a slower-
acting class of proteins derived from the
cell’s DNA.
Regardless of their origin, neurotransmitters
in the axon terminal are gathered inside
membranes that form synaptic vesicles.
Depending on the type of neurotransmitter
they house, synaptic vesicles are stored in
three ways:
1. Some are collected in storage granules.
2. Others are attached to the microfilaments in the
terminal button.
3. Still others are attached to the presynaptic
membrane, ready to release a neurotransmitter into
the synaptic cleft. When a vesicle is emptied from the
presynaptic membrane, others move to take its place
so that they, too, stand ready to release their
contents.
Voltage-sensitive calcium channels on the
presynaptic membrane play a role in triggering the
release of a neurotransmitter from a presynaptic
membrane.
The surrounding extracellular fluid is rich in calcium
ions (Ca2+).
On arrival of the action potential these voltage-
sensitive calcium channels opens, allowing an influx
of calcium into the axon terminal.
The incoming calcium ions bind to a chemical called
calmodulin, forming a molecular complex that
participates in two chemical reactions: one releases
vesicles bound to the presynaptic membrane, and the
other releases vesicles bound to filaments in the axon
terminal.
The vesicles released from the presynaptic
membrane empty their contents into the
synaptic cleft through exocytosis.
The membrane surrounding the transmitter
substances fuses with the cell membrane.
The vesicles that were formerly bound to the
filaments are then transported to the
membrane to replace the vesicles that were
just released there.
A neurotransmitter released from the
presynaptic membrane diffuses across the
synaptic cleft and binds to specialized protein
molecules in the postsynaptic membrane.
These transmitter-activated protein
molecules are called receptors because the
sites they occupy on the membrane receive
the transmitter substance.
The type of neurotransmitter and the kind of
receptors on the postsynaptic membrane
determine whether the neurotransmitter
• depolarizes the postsynaptic membrane and so has an
excitatory action;
• hyperpolarizes the postsynaptic membrane and so has
an inhibitory action;
• initiates other chemical reaction sequences that can
modulate either the excitatory or the inhibitory effect or
influence other functions of the postsynaptic neuron;
• generates new synapses; or
• brings about other changes in the cell.
In addition to acting on the postsynaptic
membrane’s receptors, a neurotransmitter
may interact with autoreceptors (self-
receptors) on its own presynaptic membrane:
it may influence the cell that just released it.
Autoreceptors receive messages from their
own axon terminal.
How much neurotransmitter is needed to send a message?
Bernard Katz (1965) was awarded a Nobel Prize in 1970 for
providing an answer.
Recording electrical activity from the postsynaptic
membranes of muscles, he detected small, spontaneous
depolarizations now called miniature postsynaptic
potentials.
The potentials varied in size, but each size appeared to be
a multiple of the smallest potential.
Katz concluded that the smallest postsynaptic potential is
produced by the release of the contents of just one
synaptic vesicle. This amount of neurotransmitter is called
a quantum.
To produce a postsynaptic potential large enough to
initiate a postsynaptic action potential requires the
simultaneous release of many quanta from the presynaptic
cell.
The results of subsequent experiments show that
the number of quanta released from the
presynaptic membrane in response to a single
action potential depends on two factors:
1. the amount of Ca2+ that enters the axon
terminal in response to the action potential and
2. the number of vesicles docked at the
membrane, waiting to be released.
Both factors affect the amplitude of a behavioral
response produced by synaptic activity and its
ability to mediate learning.
After a neurotransmitter has done its work, it
is removed quickly from receptor sites and
from the synaptic cleft to make way for other
messages sent by the presynaptic neuron.
Neurotransmitter deactivation takes place in
at least four ways:
1. Diffusion: some of the neurotransmitter simply
diffuses away from the synaptic cleft and is no longer
available to bind to receptors.
2. Degradation: Enzymes in the synaptic cleft break
down the neurotransmitter.
3. Reuptake: membrane transporter proteins
specific to that transmitter may bring the
transmitter back into the presynaptic axon
terminal for reuse. The by-products of
degradation by enzymes also may be taken
back into the terminal to be reused in the
cell.
4. Some neurotransmitters are taken up by
neighboring glial cells. Potentially, the glial
cells can also store transmitters for reexport
to the axon terminal.
As part of the flexibility of synaptic function, an axon
terminal’s chemical mechanisms enable it to respond
to the frequency of its own use.
If the terminal is very active, the amount of
neurotransmitter made and stored there increases.
For example, all synapses with muscles in the
somatic nervous system are cholinergic, using ACh as
their neurotransmitter. Changes in ACh synapse
structure and function contribute to getting in shape
as a result of intense physical exercise.
In the CNS, similar changes in the synapse contribute
to learning, memory, and performance that depend
upon the brain keeping in shape.
Synapses are an extremely versatile chemical
delivery system. In one kind, called an Axodendritic
synapse, the axon terminal of a neuron meets a
dendrite or dendritic spine of another neuron.
Another kind of synapses are
Axomuscular synapse
Axosomatic synapse
Axoaxonic synapse
Axosynaptic synapse
Axoextracellular synapses
Axosecretory synapse
Dendrodendritic synapses
Somasomatic
Despite their versatility, in the end synapses
convey only two types of messages: excitatory or
inhibitory.
That is to say, a neurotransmitter either increases
or decreases the probability that the cell it
influences will produce an action potential.
In keeping with this dual message system,
synapses can be divided into excitatory and
inhibitory categories— also known as Type I and
Type II synapses, respectively—that differ in
location and appearance.
Today, we know that the human brain
employs a wide variety of neurotransmitters,
and these chemicals work in even more
versatile ways.
Each may be excitatory at one location and
inhibitory at another, and two or more may
team up in a single synapse so that one
makes the other more potent.
The functional aspects of neurotransmitters
interrelate and are intricate, with no simple
one-to-one relation between a single
neurotransmitter and a single behavior.
1. The chemical must be synthesized in the neuron or
otherwise be present in it.
2. When the neuron is active, the chemical must be
released and produce a response in some target cell.
3. The same response (receptor action) must be obtained
when the chemical is experimentally placed on the
target.
4. A mechanism must exist for deactivating or removing
the chemical from its site of action after its work is done.
By systematically applying these criteria, researchers
can determine which of the many thousands of
chemical molecules that exist in every neuron are
neurotransmitters.
They can also synthesize transmitters and use them as
drugs.
Methodologically, identifying chemical
transmitters in the central nervous system is not
easy.
In the brain and spinal cord, thousands of
synapses are packed around every neuron,
preventing easy access to a single synapse and
its activities.
Consequently, for many substances thought to
be CNS neurotransmitters, the four criteria
needed as proof have been only partly met.
A chemical that is suspected of being a
neurotransmitter but has not yet met all the
criteria for proof is called a putative (supposed)
transmitter.
All motor-neuron axons leaving the spinal cord
are cholinergic, and each has an axon collateral
within the spinal cord that synapses on a nearby
CNS interneuron.
The interneuron, in turn, synapses on the motor
neuron’s cell body. This circular set of
connections, termed a Renshaw loop after the
researcher who first described it.
Because the main axon to the muscle releases ACh,
investigators suspected that its axon collateral also
might release it.
Knowing what chemical to look for simplified the task
of finding it and then proving that it was in fact also a
neurotransmitter in this location.
The Renshaw loop acts as a feedback circuit that
enables the motor neuron to inhibit itself and not
become overexcited in response to excitatory inputs
it receives from other parts of the CNS.
If the inhibitory neurotransmitter in the Renshaw cell,
the amino acid glycine, is blocked by the toxin
strychnine, motor neurons do become overactive,
producing convulsions that interfere with breathing,
thus causing death.
Today, the term neurotransmitter is used quite broadly. A
neurotransmitter may carry a message from one neuron to
another by influencing the voltage on the postsynaptic
membrane; it may also induce effects such as changing
the structure of a synapse.
Furthermore, researchers have discovered that
neurotransmitters communicate not only in the orthodox
fashion, by delivering a message from the presynaptic side
of a synapse to the postsynaptic side, but also in some
cases, in the opposite direction by back propagation, in
which the message is sent from the postsynaptic
membrane to the presynaptic membrane.
Finally, the original idea that each neuron had only one
transmitter at all its synapses has been supplanted:
different neurotransmitters coexist within the same
synapse, and different synapses on the same cell house
different neurotransmitters.
(1) Small molecule transmitters
(2) Neuropeptide transmitters
(3) Transmitter gases.
The first neurotransmitters identified are
quick-acting small-molecule transmitters
such as ACh.
Typically, they are synthesized from dietary
nutrients and packaged for use in axon
terminals.
When a small-molecule transmitter is
released from an axon terminal, it can quickly
be replaced at the presynaptic membrane.
Because small-molecule transmitters or their
main components are derived from food, diet
can influence their levels and activities in the
body.
This fact is important in the design of drugs
that affect the nervous system.
Many neuroactive drugs are designed to
reach the brain in the same way that small-
molecule transmitters or their precursor
chemicals do: through ingestion and
transport to the brain by the blood.
Acetylcholine (ACh)
Amines
Dopamine (DA)
Norepinephrine (NE, or noradrenaline, NA)
Epinephrine (EP, or adrenaline)
Serotonin (5-HT)
Amino Acids
Glutamate (Glu)
Gamma-aminobutyric acid (GABA)
Glycine (Gly)
Histamine (H)
ACh is made up of two substances: choline
and acetate.
Choline is among the breakdown products of
fats found in foods such as egg yolk,
avocado, salmon, and olive oil; acetate is a
compound found in acidic foods, such as
vinegar, lemon juice, and apples.
Inside the cell acetyl coenzyme A (acetyl CoA)
carries acetate to the synthesis site, and the
transmitter is synthesized as a second enzyme,
choline acetyltransferase (ChAT), transfers the
acetate to choline to form ACh.
After ACh has been released into the synaptic
cleft and diffuses to receptor sites on the
postsynaptic membrane, a third enzyme,
acetylcholinesterase (AChE), reverses the process
by detaching acetate from choline.
These breakdown products can then be taken
back into the presynaptic terminal for reuse.
The small-molecule transmitter list includes four
amines (chemicals that contain an amine group,
NH, in their chemical structure).
Some amine transmitters are synthesized by
common biochemical pathways and so are
related.
One such grouping consists of the amines
dopamine (it plays a role in coordinating
movement, in attention and learning, and in
behaviors that are reinforcing), NE (NA), and EP
(adrenaline).
The last two are the excitatory transmitters.
The precursor chemical is tyrosine, an amino
acid abundant in food. (Hard cheese and
bananas are good sources.)
The enzyme tyrosine hydroxylase changes
tyrosine into l-dopa, which is sequentially
converted by other enzymes into dopamine,
NE, and finally EP.
An interesting aspect of this biochemical
sequence is that the amount of the enzyme
tyrosine hydroxylase in the body is limited.
Consequently, so is the rate at which
dopamine, NE, and EP can be synthesized,
regardless of how much tyrosine is present or
ingested.
This rate-limiting factor can be bypassed by
orally ingesting l-dopa, which is why l-dopa
is used in the treatment of Parkinson’s
disease, a condition brought on by an
insufficiency of dopamine.
The amine transmitter serotonin (5-HT, for
5-hydroxytryptamine) is synthesized
differently.
Serotonin plays a role in regulating mood and
aggression, appetite and arousal, pain
perception, and respiration.
It is derived from the amino acid tryptophan,
which is abundant in turkey, milk, and
bananas, among other foods.
Some amino acid transmitters contain carboxyl
groups (COOH) in addition to an amine.
Two such amino acid transmitters, glutamate
(Glu) and gamma-aminobutyric acid (GABA), are
closely related: GABA is formed by a simple
modification of Glu in which one carboxyl group
is removed.
Glu and GABA are called the workhorses of the
nervous system because so many synapses use
them.
In the forebrain and cerebellum, Glu is the main
excitatory transmitter, and GABA is the main
inhibitory transmitter.
The amino acid transmitter glycine (Gly) is a
much more common inhibitory transmitter in the
brainstem and spinal cord.
Histamine (H) is synthetized from the amino acid
histidine.
Among its many functions, which include the
control of arousal and of waking, histamine can
cause the constriction of smooth muscles.
When activated in allergic reactions, histamine
contributes to asthma, a constriction of the
airways.
Neuropeptides, multifunctional chains of amino
acids that act as neurotransmitters, are made
through the translation of mRNA from
instructions in the neuron’s DNA.
Although these transmitters are produced in the
axon terminal in some neurons, most are
assembled on the cell’s ribosomes, packaged
inside a membrane by Golgi bodies, and
transported on the microtubule highway to the
axon terminals.
Their synthesis and transport are relatively slow
compared to those of small-molecule
transmitters. Consequently, neuropeptides form
slowly and are not replaced quickly.
Peptides have an enormous range of
functions in the nervous system, as might be
expected from the large number found there.
They serve as hormones (growth hormone),
are active in responses to stress
(corticotropin), encourage a mother to bond
with her infant (oxytocin), facilitate learning
(glucogen like peptide), and help to regulate
eating (cholecystokinin) and drinking
(vasopressin) and pleasure and pain (beta-
endorphin).
Peptides’ amino acid chains are degraded by
digestive processes, so unlike the small-
molecule transmitters, they are generally not
effective if taken orally.
If introduced into the blood, their large size
may also prevent them from crossing the
blood–brain barrier to reach the brain.
The water-soluble gases nitric oxide (NO) and
carbon monoxide (CO) further expand the
biochemical strategies that transmitter
substances display.
As water soluble gases, they are neither stored in
synaptic vesicles nor released from them in the
conventional manner; instead, they are
synthesized in the cell as needed.
Unlike classical neurotransmitters, NO is
produced in many regions of a neuron, including
the dendrites.
On synthesis, each gas diffuses away from the
site where it was made, easily crossing the cell
membrane and immediately becoming active.
Both NO and CO activate metabolic (energy-
expending) processes in cells, including those
modulating the production of other
neurotransmitters.
NO serves as a messenger in many parts of the body.
It controls the muscles in intestinal walls, and it
dilates blood vessels in brain regions that are in
active use, allowing these regions to receive more
blood.
It also dilates blood vessels in the genital organs and
is therefore active in producing penile erections in
males.
The drug sildenafil citrate (trade name Viagra), the
first widely used treatment for male erectile disorder,
acts by enhancing the action of NO. NO does not of
itself produce sexual arousal.
When a neurotransmitter is released from the
presynaptic membrane, it crosses the
synaptic cleft and binds to a receptor on the
postsynaptic cell.
What happens next depends on the receptor.
One class of receptors is excitatory and the
other is inhibitory.
An ionotropic receptor has two parts: a
binding site for a neurotransmitter and a pore
or channel through the membrane.
The pore regulates the movement of charged
atoms across a cell membrane when a
neurotransmitter binds to the binding site.
Ionotropic receptors are usually excitatory
and increase the likelihood that a neuron will
produce an action potential.
When the neurotransmitter attaches to the
binding site, the receptor changes its shape,
either opening the pore and allowing ions to
flow through it or closing the pore and
blocking the ion flow.
Because the binding of the transmitter to the
receptor is quickly followed by the opening or
closing of the pore that directly affects the
ion flow, ionotropic receptors bring about
very rapid changes in membrane voltage.
Structurally, ionotropic receptors are similar
to other types of membrane channels,
including voltage-sensitive channels.
They are composed of a number of
membrane-spanning subunits that make up
petals forming channel’s central pore.
Within the pore is a shape- changing
segment that causes the pore to open or
close, regulating the ion flow through it.
In contrast to ionotropic receptors, metabotropic
receptors are usually inhibitory, decreasing the
likelihood that a neuron will produce an action
potential.
A metabotropic receptor’s single protein spans the
cell membrane but does not possess a pore of its
own through which ions can flow.
The outer part of the receptor has a site for
transmitter binding.
The receptor’s internal part is associated with one of
a family of proteins called guanyl-nucleotide-binding
proteins (G proteins for short) that translates the
transmitter’s message into biochemical activity within
the cell.
A G protein consists of three subunits—alpha, beta,
and gamma.
The a (alpha) subunit detaches when a
neurotransmitter binds to the G protein’s associated
metabotropic receptor.
The detached a subunit then can bind to other
proteins within the cell membrane or within its
cytoplasm.
The a subunit can bind to nearby ion channels,
causing them to open or close, and in this way
regulate the cell membrane’s electrical charge.
The a subunit can also bind to other molecules and
so induce cascades of metabolic activity that can
change the cell’s activity or influence gene expression
in the cell’s nucleus.
The second effect of binding a
neurotransmitter to a metabotropic receptor
changes the cell’s biology.
The process begins when the detached a
subunit binds to an enzyme, which in turn
activates another chemical called a second
messenger. (The neurotransmitter is the first
messenger.)
A second messenger, as the name implies,
carries a message to other structures within
the cell.
The second messenger can
◦ Bind to a membrane channel, causing the channel
to change its structure and thus alter ion flow
through the membrane.
◦ Initiate a reaction that incorporates protein
molecules within the cell into the cell membrane,
for example, resulting in the formation of new ion
channels.
◦ Influence the cell’s DNA to initiate or cease gene
expression and thus regulate protein formation.
The Gβγ complex is an essential element in
the GPCR ( G protein coupled receptor)
signaling cascade.
It has two main states for which it performs
different functions.
When Gβγ is interacting with Gα it functions as
a negative regulator.
In the heterotrimer form, the Gβγ dimer
increases the affinity of Gα, which causes the
G protein to be in an inactive state.[
The idea that specific transmitters, wherever
found, form systems with a common function led
to the notion that the nervous system could be
parsed on the basis of neurotransmitter type.
When researchers began to study
neurotransmission at the synapse more than a
half-century ago, they reasoned that any given
neuron would contain only one transmitter at all
its axon terminals.
Since then, investigators have discovered that
different transmitters may coexist in the same
terminal or synapse.
Neuropeptides coexist in terminals with small-
molecule transmitters, and more than one small-
molecule transmitter may be found in a single
synapse.
In some cases, more than one transmitter may even be
packaged within a single vesicle.
All these variations result in a bewildering number of
neurotransmitter–receptor combinations, which
cautions as well against assuming a simple cause &
effect relation between a neurotransmitter and a
behavior.
Nevertheless, neurotransmission can be summarized
by concentrating on the dominant transmitter within
any given axon terminal.
