R.E.B, 4MedStudents.

com, 2003

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) Rapidly 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
1

Neurotransmitters found in the nervous system

EXCITATORY
Acetylcholine
Aspartate
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotonin

INHIBITORY
GABA
Glycine

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.
4

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.

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.


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.
Acetylcholinestrase

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.

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.
8

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.

Catecholamine Synthesis (Dopamine,

Norepinephrine and Epinephrine).
3) Third step: Hydroxylation:
This reaction is catalyzed by the enzyme dopamine - hydroxylase.
The reactants include dopamine, O2 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 Nmethyltransferase. Norepinephrine and S-adenosylmethionin
(ado-Met) form epinephrine and S-adenosyl homocysteine (adoHcy).
10

11

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.
12

13

Break down of serotonin:

Serotonin is degraded in two reactions

1) Oxidation:
5-hydroxytryptoamine + O2 + H2O

2) Dehydrogenation
5- HydroxyinodoleHydroxyinodole-3-acetaldehyde

Monoamine oxidase

5- HydroxyinodoleHydroxyinodole-3-acetaldehyde

Aldehyde dehydrogenase

5-hydroxindolehydroxindole-3-acetate
(Anion of 5-hydroxyindoleacetic acid)

14

Other Neurotransmitters:
Derived from

Enzyme

Histamine

Histidine

Histidine
decarboxylase

GABA
((-Amino
butyrate)

Glutamate

Glutamate
decarboxylase

Nitric Oxide

Arginine

Nitric Oxide
Synthase

Neurotransmitter

15

Summary:
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