Neurotransmitters Overview

of Synthesis and Metabolism

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Definition
A chemical released by one
neuron that affects another
neuron or an effector organ
(e.g., muscle, gland, blood
vessel)
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Neurotransmitters
Properties of neurotransmitters:
1) synthesized in the presynaptic neuron

2) Localized to vesicles in the presynaptic neuron

3) Released from the presynaptic neuron under
physiological conditions

4) Rabidly removed from the synaptic cleft by uptake or
degradation

5) Presence of receptor on the post-synaptic neuron.

6) Binding to the receptor elicits a biological response
R.E.B, 4MedStudents.com, 2003
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Neurotransmitters found in the nervous system
EXCITATORY
Acetylcholine
Aspartate
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotonin
INHIBITORY
GABA
Glycine


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Acetylcholine synthesis:

In the cholinergic neurons acetylcholine is
synthesized from choline. This reaction is
activated by cholineacetyltransferase

As soon as acetylcholine is synthesized,
it is stored within synaptic vesicles.
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Release of acetylcholine from
presynaptic neurons:
1)When the nerve impulse (Action potential) moves down the presynaptic
axon to the terminal bulb the change in the membrane action potential
causes the opening of voltage gated calcium channels open allowing Ca
2+
ions to pass from the synaptic cleft into the axon bulb.

2) Within the bulb the increase
in Ca
2+
concentration causes the
synaptic vesicles that contain
acetylcholine to fuse with the
axonal membrane and open
spilling their contents into
the synaptic cleft.

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Binding of acetylcholine to the
postsynaptic receptors:
The postsynaptic membrane of the receptor dendrite has specific cholinergic
receptors toward which the neurotransmitter diffuses. Binding of acetylcholine
trigger the opening of ion channels in the postsynaptic membrane initiating action
potential that can pass in the next axon.

Acetylcholine receptors:
Acetylcholine receptors are ion channels receptors made of
many subunits arranged in the form [(2)()()()].

When Acetylcholine is not bounded to the receptors, the
bulky hydrophobic leu side close the central channels
preventing the diffusion of any ions.
Binding of two acetylcholine molecules to the receptors will
rotate the subunits in which the smaller polar residues will line
the ion channel causing the influx of Na+ into the cell and
efflux of K+ resulting in a depolarization of the postsynaptic
neuron and the initiation of new action potential.


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Removal of Acetylcholine from the synaptic
cleft:
In order to ready the synapse for another impulses:
1) The neurotransmitters, which are released from the synaptic vesicles, are
hydrolyzed by enzyme present in the synaptic cleft Acetylcholinestrase
giving choline, which poorly binds to acetylcholine receptors.


Acetylcholine + H2O Choline + H+ acetate

2) The empty synaptic vesicles, which are returned to the axonal terminal
bulb by endocytosis, must be filled with acetylecholine.

Acetylcholinestrase
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Structure of AchE
Acetylcholinesterase (AchE) is an enzyme,
which hydrolyses the neurotransmitter
acetylcholine. The active site of AChE is
made up of two subsites, both of which are
critical to the breakdown of ACh. The
anionic site serves to bind a molecule of
ACh to the enzyme. Once the ACh is
bound, the hydrolytic reaction occurs at a
second region of the active site called the
esteratic subsite. Here, the ester bond of
ACh is broken, releasing acetate and
choline. Choline is then immediately taken
up again by the high affinity choline uptake
system on the presynaptic membrane.

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Catecholamine Synthesis (Dopamine,
Norepinephrine and Epinephrine).
1) First Step: Hydroxylation:
In this step: the reaction involves the conversion of tyrosine, oxygen
and tetrahydrobiopterin to dopa & dihydrobiopterin. This
reaction is catalyzed by the enzyme tyrosine hydroxylase. It is
irreversible reaction.
2) Second step: Decarboxylation:
In this step: the dopa decaboxylase will catalyze the decaoxylation of
dopa to produce dopamine. The deficiency of this enzyme can cause
Parkinsons disease. It is irreversible reaction. The cofactor in this
reaction is the PLP (pyridoxal phosphate). In the nerve cells that
secrete dopamine as neurotransmitter the pathway ends at this step.

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3) Third step: Hydroxylation:
This reaction is catalyzed by the enzyme dopamine - hydroxylase.
The reactants include dopamine, O
2
and ascorbate (vitamin C).
The products are norepinephrine, water and dehydroascorbate. It
is an irreversible reaction). The end product in noradrenergic cells
is norepinephrine and the pathway ends her.
4) Forth step: Methylation:
This reaction is catalyzed by phenylethanolamine N-
methyltransferase. Norepinephrine and S-adenosylmethionin
(ado-Met) form epinephrine and S-adenosyl homocysteine (ado-
Hcy).


Catecholamine Synthesis (Dopamine,
Norepinephrine and Epinephrine).
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Serotonin synthesis:

Serotonin is synthesized from the amino acid Tryptophan.
The synthesis of serotonin involve two reactions:
1) 1) Hydroxylation:
Tryptophan 5- Hydroxytryptophan
The enzyme catalyzes this reaction is Tryptophan Hydroxylase.
The Co- factor is Tetrahydrobiopterin, which converted in this reaction to
Dihydrobiopterin.
2) 2) Decarboxylation:
5- hydroxytryptophan Serotonin
The enzyme is hydroxytryptophan decarboxylase.
Serotonin is synthesized in CNS, & Chromaffin cells.

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Break down of serotonin:
Serotonin is degraded in two recations


1) Oxidation:
5-hydroxytryptoamine + O2 + H2O 5- Hydroxyinodole-3-acetaldehyde

2) Dehydrogenation
5- Hydroxyinodole-3-acetaldehyde 5-hydroxindole-3-acetate
(Anion of 5-hydroxyindoleacetic acid)

Monoamine oxidase
Aldehyde dehydrogenase

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Other Neurotransmitters:

Neurotransmitter

Derived from

Enzyme

Histamine

Histidine

Histidine
decarboxylase

GABA
(-Amino
butyrate)

Glutamate

Glutamate
decarboxylase

Nitric Oxide

Arginine

Nitric Oxide
Synthase





Neurotransmitter
Molecule


Derived
From

Site of Synthesis

Acetylcholine


Choline


CNS, parasympathetic nerves

Serotonin
5-Hydroxytryptamine (5-HT)

Tryptophan


CNS, chromaffin cells of the gut, enteric
cells

GABA


Glutamate


CNS

Histamine


Histidine


hypothalamus

Epinephrine
synthesis pathway

Tyrosine

adrenal medulla, some CNS cells


Norpinephrine
synthesis pathway

Tyrosine

CNS, sympathetic nerves


Dopamine
synthesis pathway

Tyrosine

CNS


Nitric oxide, NO


Arginine


CNS, gastrointestinal tract

Summary:
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
1. It must be synthesized in the presynaptic
neuron -
Proof = Biochemical evidence (the biosynthetic
enzymes are present in the presynaptic neuron)
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
(contd)
2. It must be present in the presynaptic neuron and
released in adequate quantities to serve as the
transmitter at the synapse
Proof = Anatomical the labeled transmitter
must be present in the presynaptic terminals (e.g.,
feed cell labeled precursors)
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
(contd)
2. It must be present in the presynaptic neuron and
released in adequate quantities to serve as the
transmitter at the synapse
Proof = Physiological Collect substance as it is
released from the presynaptic neuron and
demonstrate that this amount can cause the
appropriate postsynaptic response. (NOTE: This
has only been done for Ach at the NMJ!)
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
(contd)
3. When applied exogenously or when its agonists
(produce same effect as neurotransmitter) or
antagonists (oppose effects of neurotransmitter)
are applied to the postsynaptic cell, appropriate
responses by the postsynaptic cell must be
elicited
Proof = Pharmacological - opens appropriate
channel, activates appropriate 2
nd
messenger
system, etc.
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
(contd)
4. A specific mechanism exists to terminate the
presynaptic signal
Proof = demonstrate one of the following mechanisms
1. enzymatic breakdown e.g., Ach: Acetylcholine
esterase is synthesized and released by the muscle cell
into the basal lamina of the neuromuscular junction.
The enzyme cleaves Ach into choline and acetate to
terminate the signal. The motor neuron has transporters
for choline, used in resynthesis of Ach.
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
(contd)
4. A specific mechanism exists to terminate the
presynaptic signal
Proof = demonstrate one of the following
mechanisms
2. presynaptic reuptake e.g., Amino acid
and biogenic amines use transporters in the
presynaptic neuron or surrounding astrocytes to
remove signal from synapse.
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
(contd)
4. A specific mechanism exists to terminate the
presynaptic signal
Proof = demonstrate one of the following
mechanisms
3. diffusion no longer clear how significant
this mechanism is remember the tripartite
synapse
The Four Criteria that a Chemical Must
Meet to be Called a Neurotransmitter
(contd)
Note how important demonstration that 1) the suspected
transmitter is present in/released by the presynaptic
neuron in adequate quantities to produce an appropriate
postsynaptic response, and, 2) that pharmacological
manipulations produce predicted responses are to
documenting a chemicals role as a neurotransmitter.
Particularly since very common substances such as
glutamate and glycine are purported neurotransmitters
Classes of Neurotransmitters
A. Small Molecule Transmitters (classical
transmitters) synthesized in cytoplasm from
compounds of intermediary metabolism
Acetylcholine
Biogenic Amines (dopamine, norepinephrine, epinephrine,
serotonin, histamine)
Amino Acids (gamma-amino butyric acid = GABA,
glycine, glutamate)
Nitric oxide small diatomic gas that is also a free radical

Classes of Neurotransmitters
B. Neuroactive Peptides synthesized on rough ER and
processed for secretion by the Golgi apparatus
1. Hypothalamic-releasing Hormones
2. Neurohypophyseal Hormones (vasopressin = ADH
and oxytocin)
3. Adenohypophyseal Hormones (e.g., Growth
hormone, endorphins, melanocyte-stimulating
hormone)
4. Gastrointestinal Peptides (e.g., Gastrin, substance
P, insulin, glucagon, vasoactive intestinal peptide)
5. Others (angiotensin, bradykinin, sleep peptides)
HOWEVER, IT IS DEBATEABLE WHETHER
THESE ARE NEUROTRANSMITTERS OR A
CLASS BY THEMSELVES: HORMONES
HOWEVER, IT IS DEBATEABLE WHETHER
THESE ARE NEUROTRANSMITTERS OR A
CLASS BY THEMSELVES: HORMONES,
because

these do not fit the first 2 criteria of that
of neurotransmitter.
their actions are far-reaching, rather than
just synaptic.
Original Dales Law (1950s)
A mature neuron makes use of the same transmitter
substance at all of its synapses

Discovery of peptide transmitters

Modified Dales Law = A mature neuron makes
use of the same combination of chemical
transmitters at all of its synapses.
Modified Dales Law when co- secretion occurs, it
usually involves a small molecule transmitter and
one or more peptides
Small Molecule Transmitter

AcH

Norepinephrine


Dopamine

Epinephrine

Serotonin
Peptide

VIP

Somatostatin + enkephalin +
neurotensin

Cholecystokinin + enkephalin

Enkephalin

Substance P + TRH