NEUROTRANSMITTERS

Rajendra Dev Bhatt PhD Scholar

Asst. Professor
Clinical Biochemistry & Laboratory Medicine
Fellow: Translational Research (2018-2022) in CVD in Nepal,
NHLBI & NIH, USA
 INTRODUCTION
• A substance that is released at a synapse by a neuron and
that effects another cell, either a neuron or an effectors
organ, in a specialized manner , called neurotransmitter.
OR
Neurotransmitters are endogenous chemicals that
transmit signals from a neuron to a target cell across
a synapse
• Synapses are the junctions where neurons release a
chemical neurotransmitter that acts on a postsynaptic target
cell, which can be another neuron or a muscle or gland cell
• Some chemicals released by neurons have little or no direct
effects on their own but can modify the effects of
neurotransmitters. These chemicals are called
neuromodulators.
 Neurotransmitter Criteria
Chemical messengers must meet following criteria to be
considered transmitters:
• It is synthesized by a neuron.
• It is present in the presynaptic terminal and is
released in amounts sufficient to exert a defined
action on a postsynaptic neuron or effector
organ.
• When given as a drug, it mimics the action of
naturally occurring transmitter in the body
exactly.
• A specific mechanism exists for removing it.
THE FATHER OF NEUROSCIENCE
• Otto Loewi (German
pharmacologist)

• Discovered the chemical

nature of
neurotransmission
(Acetylcholine) across
synapse

• Loewi was awarded the

Nobel Prize in Physiology
(1936)
 CLASSIFICATION OF
NEUROTRANSMITTERS (Physiological)

EXCITATORY INHIBITORY BOTH

Glycine Acetylcholine
Glutamate

GABA Nor epinephrine

Aspartate
Serotonin

Nitric oxide
Dopamine
CLASSIFICATION OF NEUROTRANSMITTERS
(Biochemical)
 CLASSIFICATION OF NEUROTRANSMITTERS
(Pharmacological)
• Neurotransmitters can also be classified by another
way dependent upon whether the receptor activated by
the binding of transmitter is a metabotropic or an
ionotropic receptor.
• Metabotropic (muscarinic) receptors activate signal
transduction upon transmitter binding similar to many
peptide hormone receptors which involves a second
messenger. Many metabotropic receptors are members
of the Gprotein coupled receptor (GPCR) family.
• Ionotropic (nicotinic) receptors constitute an ion
channel, most often a ligand gated ion channel.
• Some neurotransmitters, for example glutamate and
acetylcholine, bind to multiple receptors some of
which are metabotropic and some of which are
ionotropic.
This acquired knowledge about the
neurotransmitters has led to the development
of successful products for many brain
disorders including epilepsy, schizophrenia,
Parkinson’s disease, depression, anxiety
disorders and migraine .
 Neurotransmitter Receptors

• Once the molecules of neurotransmitter are

released from a cell as the result of the firing of an
action potential, they bind to specific receptors on
the surface of the postsynaptic cell.
• The vast majority of neurotransmitter receptors
belong to a class of proteins known as the G-
protein coupled receptors, GPCRs.
 Acetylcholine
• Acetylcholine (ACh) is a simple molecule
synthesized from choline and acetylCoA through the
action of choline acetyltransferase.
• Neurons that synthesize and release ACh are termed
cholinergic neurons.
• When an action potential reaches the terminus of a
presynaptic neuron a voltage gated calcium channel
is opened.
• The influx of calcium ions, Ca2+, stimulates the
exocytosis of presynaptic vesicles containing ACh,
which is thereby released into the synaptic cleft.
 Choline acetyl
transferase

Once released, ACh must be removed rapidly in order to allow

repolarization to take place; this step, hydrolysis, is carried out by the
enzyme, acetylcholinesterase (AChE).

The released choline is then taken back up by the presynaptic neuron

where it can once again serve as a substrate for ACh synthesis
via choline acetyltransferase.
Two different mammalian AChE isoforms are
produced from the single ACHE gene (chromosome
7q22.1) in humans via alternative splicing and
posttranslational modification.

These two AChE isoforms are termed T (tail) and H

(hydrophobic). The T form (AChET, also known as
the hydrophilic form) is the predominant enzyme in
the brain and at the neuromuscular junction.

Two main classes of ACh receptors have been

identified on the basis of their responsiveness to the
toadstool (poisonous mushroom) alkaloid , muscarine
and nicotine.
 Acetylcholine Receptors

Muscarinic
Nicotinic
 Muscarinic receptors
• Muscarine, the alkaloid responsible for the toxicity of
toadstools, has little effect on the receptors in autonomic
ganglia but mimics the stimulatory action of acetylcholine
on smooth muscle and glands.
• These actions of acetylcholine are therefore called
muscarinic actions, and the receptors involved are
muscarinic cholinergic receptors.
• Five types, encoded by five separate genes, have been
cloned (M1-M5).
• M1 is abundant in the brain.
• The M2 receptor is found in the heart.
• The M4 receptor in pancreatic acinar and islet tissue.
• The M3 and M4 receptors are associated with smooth
muscle.
 Nicotinic receptors
• In Sympathetic Ganglia, the actions of Ach are unaffected
by atropine but MIMICKED BY NICOTINE.
Consequently, these actions of Ach are nicotinic actions and
the receptors are nicotinic cholinergic receptors.

• Nicotinic receptors are subdivided into those at

neuromuscular junctions and those found in autonomic
ganglia and the central nervous system

• Both muscarinic and nicotinic acetylcholine receptors are

found in large numbers in the brain.

• The nicotinic acetylcholine receptors are members of a super

family of ligand-gated ion channels
• Each nicotinic cholinergic receptor is made up
of five subunits that form a central channel
which, when the receptor is activated, permits
the passage of Na+ and other cations. A
prominent feature of neuronal nicotinic
cholinergic receptors is their high permeability
to Ca2+.

• The 5 subunits come from a menu of 16 known

subunits, α1–α9, β1–β5, γ , δ and ε , coded by
16 different genes.
 CATECHOLAMINES: Dopamine,
Epinephrine, Norepinephrine
•These three neurotransmitters are synthesized in a
common pathway from the amino acid tyrosine. Tyrosine
is supplied in the diet or is synthesized in the liver from the
essential amino acid phenylalanine by phenylalanine
hydroxylase.

•The tyrosine is then transported to catecholamine

secreting neurons where a series of reactions convert it to
dopamine, to norepinephrine and finally to epinephrine
 SYNTHESIS OF CATECHOLAMINES
The first and rate-limiting step in the synthesis of these
neurotransmitters from tyrosine is the hydroxylation of the
tyrosine ring by tyrosine hydroxylase, a tetrahydrobiopterin
(BH4)-requiring enzyme.

The product formed is dihydroxyphenylalanine (DOPA).

The phenyl ring with two adjacent OH groups is a catechol, and

hence dopamine, norepinephrine, and epinephrine are called
catecholamines.

The second step in catecholamine synthesis is the

decarboxylation of DOPA to form dopamine. This reaction, like
many decarboxylation reactions of amino acids, requires
pyridoxal phosphate (PLP).
Neurons that secrete norepinephrine synthesize it from
dopamine in a hydroxylation reaction catalyzed by
dopamine -hydroxylase (DBH). This enzyme is present
only within the storage vesicles of these cells.

These neurons contain the above pathway for

norepinephrine synthesis and in addition contain the
enzyme that transfers a methyl group from SAM to
norepinephrine to form epinephrine.

Thus, epinephrine synthesis is dependent on the

presence of adequate levels of B12 and folate.
Once synthesized, dopamine, norepinephrine and
epinephrine are packaged in granulated vesicles for
secretion in response to the appropriate nerve impulse.
The catecholamines are transported into vesicles by
the protein VMAT2 (vesicle membrane transporter)

The primary effects of the catecholamines are exerted

as neurotransmitters upon their stimulated release from
presynaptic nerve terminals in the appropriate target
organ.
The catecholamines are also known as adrenergic
neurotransmitters and the neurons that secrete them are
referred to as adrenergic neurons.
Catecholamines exhibit peripheral nervous system
excitatory and inhibitory effects as well as actions in
the CNS such as respiratory stimulation and an
increase in psychomotor activity.

The excitatory effects are exerted upon smooth

muscle cells of the vessels that supply blood to the
skin and mucous membranes.

Cardiac function is also subject to excitatory effects,

which lead to an increase in heart rate and in the
force of contraction.
Inhibitory effects, by contrast, are exerted
upon smooth muscle cells in the wall of the
gut, the bronchial tree of the lungs, and the
vessels that supply blood to skeletal muscle.

The actions of norepinephrine and

epinephrine are exerted upon binding to and
activating the adrenergic receptors of which
are nine distinct forms.
 Catecholamine Catabolism
The action of catecholamines is terminated through
reuptake into the presynaptic terminal and diffusion
away from the synapse. Degradative enzymes are
present in the
presynaptic terminal, and in adjacent cells, including
glial cells and endothelial cells.

Epinephrine and norepinephrine are catabolized to

inactive compounds through the sequential actions of
catecholamine O methyltransferase (COMT) and
monoamine oxidase (MAO).
Serotonin (5hydroxytryptamine, 5HT)
• Serotonin, an inhibitory neurotransmitter, is formed in the
body by hydroxylation and decarboxylation of the essential
amino acid TRYPTOPHAN
• Tryptophan hydroxylase in the human CNS is slightly
different from the tryptophan hydroxylase in peripheral
tissues, and is coded by a different gene.
The greatest concentration of 5HT (90%) is found in the
enterochromaffin cells of the gastrointestinal tract.
Most of the remainder of the body's 5HT is found in platelets
and the CNS.

The effects of 5HT are felt most prominently in the

cardiovascular system, with additional effects in the respiratory
system and the intestines. Vasoconstriction is a classic response
to the administration of 5HT.

Neurons that secrete 5HT are termed serotonergic. Following

the release of 5HT, a portion is taken back up by the
presynaptic serotonergic neuron in a manner similar to that of
the reuptake of norepinephrine.
• After release from
serotonergic neurons, much
of the released serotonin is
recaptured by an active
reuptake mechanism and
inactivated by
MONOAMINE
OXIDASE (MAO) to form
5-hydroxyindoleacetic acid
(5-HIAA).

• This substance is the

principal urinary metabolite
of serotonin, and its urinary
output is used as an index
of the rate of serotonin
metabolism in the body
 Serotonergic Receptors
• 5-HT1 - 5-HT7 receptors
• Most of these are G protein-coupled receptors

• 5-HT3 receptors are ligand-gated ion channels

present in the GIT & related to vomiting.
 Histamine
• Histamine, an excitatory neurotransmitter, referred
as a biogenic amine which is a potent
neurotransmitter that binds to specific histamine
receptors .

• Histamine is synthesized by the enzymatic

decarboxylation of the amino acid histidine by the
enzyme histidine decarboxylase (HDC).

• Within the gastrointestinal tract bacteria also

produce histamine via a similar decarboxylation
reaction.
Following its release, histamine is metabolized by two
alternative pathways, one of which is an oxidation and
the other a methylation reaction.
• The oxidation of histamine is catalyzed by a
diamine oxidase encoded by the AOC1 (amine
oxidase, copper containing 1) gene. The
product of diamine oxidase reaction is
imidazole acetaldehyde which is itself further
metabolized to imidazole acetate via the
action of an aldehyde dehydrogenase.
• The methylation of histamine is catalyzed by
the enzyme histamine Nmethyltransferase
encoded by the HNMT gene.
• Humans express four distinct histamine
receptors identified as H1R, H2R, H3R, and H4R.
All four histamine receptors are members of the
G protein coupled receptor super family.
 Glutamate & GABA
Within the CNS glutamate is the main excitatory
neurotransmitter. Neurons that respond to glutamate are referred
to as glutamatergic neurons.

Glutamate is primarily synthesized from the TCA cycle

intermediate –ketoglutarate.

This can occur via either of two routes. The first is via the
enzyme glutamate dehydrogenase, which reduces -ketoglutarate
to glutamate.

The second route is through transamination reactions in which

an amino group is transferred from other amino acids to -
ketoglutarate to form glutamate.
GABA (Gama-aminobutyric acid) is the major inhibitory
neurotransmitter in the central nervous system.

GABA is synthesized by the decarboxylation of glutamate in a

single step catalyzed by the enzyme glutamic acid
decarboxylase (GAD).
GABA is recycled in the central nervous system by a series of
reactions called the GABA shunt, which conserves glutamate
and GABA
GABA exerts its effects by binding to two distinct
receptor subtypes. The GABA-A (GABAA) receptors are
members of the ionotropic receptors, specifically the
subfamily of ligandgated ion channels.

The GABA-B (GABAB) receptors belong to the class C

family of metabotropic G protein coupled receptors
(GPCR).
 Glycine
• Glycine is the major inhibitory neurotransmitter
in the spinal cord. Most of the glycine in neurons
is synthesized de novo within the nerve terminal
from serine by the enzyme serine
hydroxymethyltransferase, which requires folic
acid. Serine, in turn, is synthesized from the
intermediate 3-phosphoglycerate in the
glycolytic pathway.
 ASPARTATE

• Aspartate, like glutamate, is an excitatory

neurotransmitter, but it functions in far fewer
pathways. It is synthesized from the TCA cycle
intermediate oxaloacetate via transamination
reactions.
 NITRIC OXIDE
• Nitric oxide (NO) is a biologic messenger in a variety
of physiologic responses, including vasodilation,
neurotransmission, and the ability of the immune
system to kill tumor cells and parasites.
• First described in 1979 as a potent relaxant of
peripheral vascular smooth muscle.
• Used by the body as a signaling molecule.
• Serves different functions depending on body system.
i.e. neurotransmitter, vasodilator, bactericide.
• Environmental Pollutant
• First gas known to act as a biological messenger
• Nitric oxide is a diatomic free radical consisting of
one atom of nitrogen and one atom of oxygen
• Lipid soluble and very small for easy passage
between cell membranes
• Short lived, usually degraded or reacted within a
few seconds
 Synthesis of Nitric Oxide
• NO is synthesized from arginine in a reaction
catalyzed by NO synthase.
 How does NO work?

• Diffuses to cells other than the one where it

was synthesised
• cGMP acts to sequester intracellular calcium
and close calcium channels
• Drop in intracellular calcium causes relaxation
 Functions of NO in body
• Dilates blood vessels
• Displaces oxygen from oxyhaemoglobin
• ‘metabolic factor’ mediating increased blood flow
to exercising muscle
• Appears to prevent hypoxia
• Released from organic nitrate and nitrite
vasodilators
• Acts to relax bronchial smooth muscle
• NO is oxidised to nitrite and then nitrate excreted
in urine
Thank You…