Introduction to
Neurotransmitters
By: Rahmad Abdillah
PROFIL
Live in Padang
Minangnese
apt. Rahmad Abdillah., M.Si
Education:
Magister Pharmacology &
Toxicology
Affiliation
Faculty of Pharmacy
198910242019031014 Universitas Andalas
Objective
After studying this chapter, you should be able to:
• List the major types of neurotransmitters and neuromodulators that are
broadly characterized as small-molecule transmitters, large-molecule
transmitters, and gas transmitters.
• Summarize the five common steps involved in the biosynthesis, release,
action, and removal from the synaptic cleft of the major small-molecule
and large-molecule neurotransmitters.
• Recognize the major distribution of the various types of receptors that
mediate the functional responses of the common neurotransmitters:
amino acids (glutamate and GABA), acetylcholine, monoamines
(norepinephrine, epinephrine, dopamine, and serotonin), and opioid
peptides.
• List receptor antagonists for each of the common neurotransmitters.
Introduction
Neurotransmitters are chemical messengers that transmit
signals from a neuron to a target cell across a synapse.
Target cell may be a neuron or some other kind of cell like a
muscle or gland cell.
Necessary for rapid communication in synapse.
Neurotransmitters are packaged into synaptic vesicles -
presynaptic side of a synapse
Vesicles (containing
neurotransmitters)
Synaptic cleft
Receptors
Receiving neuron
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
condition
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
Chemistry of Transmitters
• Many neurotransmitters and the enzymes involved in their synthesis and
catabolism are localized in nerve endings.
• There are three main classes of chemical substances that serve as
neurotransmitters and neuromodulators:
1. Small molecule transmitters (eg, glutamate, γ-aminobutyric acid [GABA], and
glycine), acetylcholine, and monoamines (eg, norepinephrine, epinephrine,
dopamine, and serotonin).
2. Large-molecule transmitters include neuropeptides such as substance P,
enkephalin, and vasopressin.
3. Gas transmitters include nitric oxide (NO) and carbon monoxide (CO)
Types of Neurotransmitters
EXCITATORY INHIBITORY BOTH
Glycine Acetylcholine
Glutamate
GABA Nor epinephrine
Aspartate
Serotonin
Nitric oxide
Dopamine
Classes of CNS Transmitters
ACETYLCHOLINE (ACh)
Acetylcholine was the first neurotransmitter to be discovered.
Isolated in 1921 by a German biologist named Otto Loewi.
Uses choline as a precursor - cholinergic neurotransmitter. Acetylcholine is the
transmitter at the neuromuscular junction, in autonomic ganglia, and in postganglionic
parasympathetic nerve-target organ junctions and some postganglionic sympathetic
nerve-target junctions.
Used by the Autonomic Nervous System, such as smooth muscles of the heart, as an
inhibitory neurotransmitter.
Responsible for stimulation of muscles, including the muscles of the gastro-
intestinal system.
Used everywhere in the brain.
Related to Alzheimer's Disease.
ACETYLCHOLINE (ACh)
• Acetylcholine is released when a nerve impulse
triggers the influx of Ca2+ into the nerve terminal
transported into the presynaptic nerve terminal by
a Na+-dependent choline transporter (CHT), which
can be blocked by the drug hemicholinium
• Acetylcholine must be rapidly removed from the
synapse if repolarization is to occur. The removal
occurs by way of hydrolysis of acetylcholine to
choline and acetate, a reaction catalyzed by the
enzyme acetylcholinesterase in the synaptic cleft.
Biochemical events at a cholinergic synapse
Dopamine
Is synthesized in three steps from the amino acid tyrosine.
Associated with reward mechanisms in brain.
Generally involved in regulatory motor activity, in mood, motivation and
attention.
Schizophrenics have too much dopamine.
Patients with Parkinson's Disease have too little dopamine.
Dopamine
• Dopamine is transported from the cytoplasm into the
vesicle by the vesicular monoamine transporter
(VMAT), which can be blocked by the drug reserpine.
NE and other amines can also be carried by VMAT.
• Dopamine is converted to NE in the vesicle.
• Once dopamine is synthesized, it is transported into
the vesicle by the VMAT.
Norepinephrine (Adrenaline)
Synthesized directly from dopamine.
Direct precursor to epinepherine.
It is synthesized in four steps from tyrosine.
Synthesized within vesicles.
Norepinephrine is strongly associated with bringing our nervous systems
into "high alert."
It increases our heart rate and our blood pressure. It is also important for
forming memories.
Glutamate
• The amino acid glutamate is the main excitatory neurotransmitter in
the brain and spinal cord and may be responsible for 75% of the
excitatory transmission in the CNS.
• There are two distinct pathways involved in the synthesis of
glutamate
1. α-ketoglutarate produced by the Krebs cycle is converted to glutamate by
the enzyme GABA transaminase (GABA-T)
2. Second pathway, glutamate is released from the nerve terminal into the
synaptic cleft by Ca2+-dependent exocytosis and transported via a
glutamate reuptake transporter into glia, where it is converted to
glutamine by the enzyme glutamine synthetase
Glutamate
• (Glu) released into the synaptic cleft by Ca2+-
dependent exocytosis.
• Released Glu can act on ionotropic and G-
protein-coupled receptors on the postsynaptic
neuron.
• In glia, Glu is converted to glutamine (Gln) by the
enzyme glutamine synthetase; Gln then diffuses
into the nerve terminal where it is hydrolyzed
back to Glu by the enzyme glutaminase.
• In the nerve terminal, Glu is highly concentrated
in synaptic vesicles by a vesicular glutamate
transporter
γ-AMINO BUTYRIC ACID (GABA)
Synthesized directly from glutamate.
GABA is the major inhibitory mediator in the brain and mediates
both presynaptic and postsynaptic inhibition.
Present in high concentrations in the CNS, preventing the brain
from becoming overexcited.
If GABA is lacking in certain parts of the brain, epilepsy results.
Serotonin (5-HT)
Synthesized in two steps from the amino acid tryptophan
Regulates attention and other complex cognitive functions, such
as sleep (dreaming), eating, mood, pain regulation.
Too little serotonin has been shown to lead to depression,
anger control etc.
• Serotonin is transported into the vesicles
by the VMAT.
• After release from serotonergic neurons,
serotonin is recaptured by the relatively
selective serotonin transporter (SERT).
• Once serotonin is returned to the nerve
terminal, it is either taken back into the
vesicles or is inactivated by MAO to form
5- hydroxyindoleacetic acid (5-HIAA)
Receptors
• The action of a chemical mediator on its target structure is more dependent on
the type of receptor on which it acts than on the properties of the mediator.
• There are five ligands-receptors binding.
1. Each chemical mediator has the potential to act on many subtypes of
receptors. For example, norepinephrine acts on α1-, α2-, β1-, β2-and β3-
adrenergic receptors. This multiplies the possible effects of a given ligand and
makes its effects in each cell more selective
2. Receptors for many neurotransmitters are located on both presynaptic and
postsynaptic elements. A presynaptic receptor called an autoreceptor often
inhibits further release of the transmitter, providing feedback control. Ex:
norepinephrine acts on α2-presynaptic receptors to inhibit additional
norepinephrine release.
A presynaptic heteroreceptor is one whose ligand is a chemical other than the
transmitter released by the nerve ending on which the receptor is located. For
example, norepinephrine acts on a heteroreceptor on a cholinergic nerve
terminal to inhibit the release of acetylcholine. In some cases, presynaptic
receptors facilitate the release of neurotransmitters.
Receptors
3. Receptors are grouped into two large families based on structure and
function: ligand-gated channels (also known as ionotropic receptors)
and metabotropic receptors (also known as G-protein-coupled
receptors [GPCRs]). In the case of ionotropic receptors, a membrane
channel is opened when a ligand binds to the receptor; and activation of the
channel usually elicits a brief (few to tens of milliseconds) increase in ionic
conductance. Thus, these receptors are important for fast synaptic
transmission.
Receptors
4. Receptors are concentrated in
clusters on the postsynaptic
membrane close to the endings of
neurons that secrete the
neurotransmitters specific for
them. This is generally due to the
presence of specific binding
proteins for them.
Receptors
5. In response to prolonged exposure to their ligands, most receptors
become unresponsive; that is, they undergo desensitization. This
can be of two types: homologous desensitization, with loss of
responsiveness only to the ligand and maintained responsiveness of
the cell to other ligands; and heterologous desensitization, in
which the cell becomes unresponsive to other ligands as well.
Steps In Neurotransmitter Processing
• Synthesis:Neurotransmitters are synthesized by the enzymatic
transformation of precursors.
• Storage: They are packaged inside synaptic vesicles
• Release: They are released from presynaptic terminal byexocytosis
when calcium enters axon terminal during an action
potential diffuse across the synaptic cleft to the
postsynaptic membrane
• Binding: They bind to receptor proteins.
• Inactivation: The neurotransmitter is degraded either by being
broken down enzymatically, or reused by active reuptake.
Thank You
