Neurotransmitters

By:- Behailu Tsegaye

 Outline of the presentation

 Introduction
 Neurotransmitters
 Neurotransmitter Synthesis and action
 Classification of neurotransmitters
 Objective

By the end of this lecture you are able to

 Understood about Neurotransmitter

 Identify how Neurotransmitter can work
 Classify Neurotransmitter
 Mention different types of Neurotransmitter
 Introduction

Neurons are
composed of

Dendrites: receive
information and pass it to
cell body
Cell Body: summarizes
information
Axon: extends from cell
body, carries electrical
potential, sends a
chemical message to
adjacent neurons
 INFORMATION EXCHANGE IN THE NERVOUS SYSTEM
• Neurons constantly relay information between each other, and
also between themselves and their environment. Information is
transmitted from cell to cell using the following forms:
 axon to dendrite – axodendritic exchange
 axon to cell body – axosomatic exchange
 axon to axon – axoaxonic exchange
 dendrite to dendrite – dendrodendritic exchange
 Synapes
Synapse is a junction between the
axon tip of the sending neuron and the
dendrite or cell body of the receiving
neuron. Is made of 4 components:
1. Terminal button - Enlarged
area at the axon terminal
2. Synaptic vesicles - Sacs in the
terminal button that release
chemicals called
neurotransmitters into the
synaptic space
3. Synaptic space (synaptic cleft)
- Tiny gap between neurons
4. Receptor sites - Location on
receptor neuron where
neurotransmitters can bind.
 The Action Potential and Nerve Impulse
• When cell membrane at rest it is not receiving any information from
other neurons; in this state, it is said to be at the resting membrane
potential
• At rest intracellular fluid of a neuron is more negatively charged than
the extracellular fluid, and this polarity difference is termed the resting
potential
• The resting membrane potential of a neuron is about - 70 millivolts
(mV)
• There is more sodium (Na+ ) on the outside of the cell than potassium
(K+ ) on the inside
• Sodium/potassium pump are responsible for the distribution of
electrically charge
 Cont..
• The membrane resting potential is present when a
neuron is at rest. However, when our nervous system
transmits information, an action potential or a nerve
impulse occurs.
• An action potential is a short-term event in which the
electrical membrane potential of a cell rapidly increases
and falls. Positive ions flowing into the cell will reduce
the negative charge and thus reduce the charge across
the entire membrane; we refer to this as depolarization
 Cont..
• When depolarisation gets to around –55 mV, a
neuron will give off an action potential
• When Na+ enters, the membrane potential
increases, and K+ exits
• Na+ channels then start to go back to their normal
closed state, which causes the action potential to
revert towards –70 mV (a repolarisation).
 Neurotransmitters
• Neurotransmitters are chemical messengers that carry
chemical signals (“messages”) from one neuron (nerve
cell) bind to receptor proteins in the cellular membrane of
the next target cell.
• The next target cell can be another nerve cell, a muscle
cell or a gland and gets excited, inhibited, or functionally
modified in some other way.
• Neurotransmitters are substances which neurons use to
communicate with one another and with their target tissues
in the process of synaptic transmission
(neurotransmission). 
 Cont..
• These messages help to move your limbs, feel sensations, keep
your heart beating, and take in and respond to all information to the
body receives from other internal parts of your body and your
environment.
• Nervous system controls everything from mind to muscles, as well
as organ functions.
• In other words, nerves are involved in everything you do, think
and feel.
• Your nerve cells send and receive information from all body
sources.
• This constant feedback is essential to your body’s optimal function.
 Cont..
Nervous system controls functions of:
 Heartbeat and blood pressure
 Breathing
 Muscle movements
 Thoughts, memory, learning and feelings
 Sleep, healing and aging
 Stress response
 Hormone regulation
 Digestion, sense of hunger and thirst
 Senses (response to what you see, hear, feel, touch and taste)
 Neurotransmitter Synthesis and action
 Most of these
neurotransmitters are
synthesized in the
neuron and localized
in the cytoplasm of
the presynaptic
terminal
 Synthesis from
 Amino acids
 Intermediates of
glycolysis
 TCA cycle, and O2

some neurotransmitters
(epinephrine, serotonin, and
histamine) are also secreted
by cells other than neurons
 Cont..
 Once synthesized, the neurotransmitters are
transported into storage vesicles by an ATP-
requiring pump linked with the proton gradient
and via neuro-filaments and microtubules
 Release from the storage vesicle is triggered by
the nerve impulse that depolarizes the
postsynaptic membrane and causes an influx of
Ca2+ ions through voltage-gated calcium
channels.
 The influx of Ca2+ promotes fusion of the
vesicle with the synaptic membrane and release
of the neurotransmitter into the synaptic cleft.
 The transmission across the synapse is
completed by binding of the neurotransmitter to
a receptor on the postsynaptic membrane
 Cont..
• Neurotransmitters are located in a part of
the neuron called the axon terminal.
They’re stored within thin-walled sacs
called synaptic vesicles. Each vesicle can
contain thousands of neurotransmitter
molecules.
• As a message or signal travels along a
nerve cell, the electrical charge of the
signal causes the vesicles of
neurotransmitters to fuse with the nerve
cell membrane at the very edge of the cell.
• The neurotransmitters, which now carry
the message, are then released from the
axon terminal into a fluid-filled space
that’s between one nerve cell and the next
target cell (another nerve cell, muscle cell
or gland).
 Cont..
• Each type of neurotransmitter
lands on and binds to a
specific receptor on the target
cell
• After binding, the
neurotransmitter then triggers
a change or action in the target
cell, like an
 electrical signal in another
nerve cell,
 a muscle contraction or
 the release of hormones
from a cell in a gland.
 Cont..
 The action of the neurotransmitter is terminated
through

 Reuptake into the presynaptic terminal

 Uptake into glial cells
 Diffusion away from the synapse, or
 Enzymatic inactivation
 The enzymatic inactivation may occur in the
postsynaptic terminal, the presynaptic terminal or an
adjacent astrocyte microglia cell, or in endothelial
cells in the brain capillaries
The action of the
neurotransmitters
stops:
(i) as they dilute by
diffusion in the
synaptic cleft
(ii) by hydrolysis
through the action of
enzymes there
 What action or change do neurotransmitters transmit to the
target cell?

• Neurotransmitters transmit one of three possible

actions in their messages, depending on the specific
neurotransmitter.
• Excitatory :- Excitatory neurotransmitters “excite”
the neuron and cause it to “fire off the message,”
meaning, the message continues to be passed along to
the next cell.
• Depolarization of post synaptic membrane

Examples :- glutamate, epinephrine and

norepinephrine.
 Cont..
• Inhibitory. Inhibitory neurotransmitters block or
prevent the chemical message from being passed along
any farther
• hypo polarization of post synaptic membrane

Example:- Gamma-aminobutyric acid (GABA), glycine

and serotonin
 Cont..
• Modulatory. Modulatory neurotransmitters influence the
effects of other chemical messengers. They “tweak” or
adjust how cells communicate at the synapse. They also
affect a larger number of neurons at the same time.
• Altering neuron activity by amplifying or damping
synaptic activity

eg. Dopamine (DA)

Serotonin (5-HT)
Acetylcholine (ACh)
Histamine
Norepinephrine (NE)
 Cont..
Glutamate (Glu)
Acetylcholine (ACh)
Histamine
Excitatory neurotransmitters
Dopamine (DA)
Norepinephrine (NE); also known as noradrenaline (NAd)
Epinephrine (Epi); also known as adrenaline (Ad)

gamma-Aminobutyric acid (GABA)

Inhibitory neurotransmitters Serotonin (5-HT)
Dopamine (DA)

Dopamine (DA)
Serotonin (5-HT)
Neuromodulators Acetylcholine (ACh)
Histamine
Norepinephrine (NE)

Releasing hormones from hypothalamus

Neurohormones Oxytocin (Oxt)
Vasopressin; also known as antidiuretic hormone (ADH)  25
 Cont..
• Neurotransmitters act in two ways:

 Direct and Indirect

 In direct action:-the neurotransmitter opens ion channels by
binding to a channel-linked receptor; this causes very fast
responses.
Examples are amino acids and AChE.
 In indirect action:- the action takes place via a G-protein-linked
receptor, and when the neurotransmitter binds it causes a cascade
of intracellular second messenger systems; this generally has long-
lasting effects.
Examples are soluble gases such as NO, and neuropeptides.
26
 Neurotransmitter Receptors
• Once released, neurotransmitter molecules diffuse across
the synaptic cleft
• When they arrive postsynaptic membrane , they bind to
neurotransmitter receptors

• Two types of receptors

 Ionotropic Receptors (Ligand-gated Ion Channels)
 Metabotropic Receptors (G Protein-gated Ion Channels)

27
Neurotransmitters Receptor types

Ionotropic
It is the receptors work very fast and play an important role in fast
neurotransmission. It is open ionic gates and allow the flow of current
through the postsynaptic membrane (eg., Ach).

It can stated to be

Ionotropic Receptors
Ligand-gated Ion Channels
Directly-gated Ion Channels

28
Cont..
 At the center of the receptor is a channel or pore to allow flow of
neurotransmitter, leading to generation of physiological effects.
 At rest, receptor channels are closed, and when neurotransmitter
binds to the channel, it immediately opens. When ligand leaves
binding site, channel quickly closes.

29
Cont..
Metabotropic: slower, longer lasting change, affecting cellular
permeability.. (using G Proteins, Ca2+, calmodulin, cAMP...)
(eg., NE).

Metabotropic Receptors
G Protein-gated Ion Channels Although it takes longer for postsynaptic cell to respond,
Indirectly-gated Ion Channels

30
Cont..

31
G protein-coupled receptors
Classification of neurotransmitters
• There are more than 40 neurotransmitters in the human
nervous system; some of the most important are

 Acetylcholine
 Norepinephrine
 Dopamine
 gamma-aminobutyric acid (GABA)
 glutamate
 serotonin
 histamine
 Gamma-Aminobutyric acid (GABA)
 GABA is the most powerful inhibitory neurotransmitter produced
by the neurons of the spinal cord, cerebellum, basal ganglia, and
many areas of the cerebral cortex.
 Functions of GABA are closely related to mood and emotions by
reducing neuronal excitability throughout the nervous system
 It regulates brain activity to prevent problems in the areas of
anxiety, irritability, concentration, sleep, seizures and depression
 It is produced by decarboxylation of glutamate, in a single step
catalyzed by the enzyme glutamic acid decarboxylase (GAD).

35
• GABA is recycled in the central
nervous system by a series of
reactions called the GABA
shunt, which conserves
glutamate and GABA
• Much of the uptake of GABA
occurs in glial cells. The GABA
shunt in glial cells produces
glutamate, which is converted to
glutamine and transported out of
the glial cells to neurons, where
it is converted back to glutamate.
• Glutamine thus serves as a
transporter of glutamate between
cells in the CNS.
• Glial cells lack GAD and cannot
synthesize GABA.
• GABA’s activity ends with
reuptake, just as with any other
amino acid neurotransmitter.
• GABA A and GABA B are the
most analysed of the five types
of GABA receptors
• Several disorders have been
connected to GABA receptors;
dysfunction with this inhibitory
neurotransmitter can cause
seizures and anxiety disorders
Clinical Correlates

 GABA promotes neuron

inhibition by promoting
entry of chloride into the
neuron. Numerous
pharmacologic agents (i.e.,
benzodiazepines,
topiramate, lamotrigine,
and tiagabine) stimulate
GABA activity in the
treatment of seizures and
other hyperspastic
disorders.
38
 Glutamate (Glu)
• It is the most powerful excitatory neurotransmitter of the
central nervous system which leading to the depolarization
of neurons
• It is secreted by neurons of the many of the sensory
pathways entering the central nervous system, as well as the
cerebral cortex. 
• It takes part in the regulation of general excitability of the
central nervous system, learning processes, and memory.
• Thus, inappropriate glutamate neurotransmission contributes
to developing epilepsy and cognitive and affective disorders.
 Synthesis of Glutamte
• Glutamate is synthesized de novo from glucose rather than taken up
from the blood because its plasma concentration is low and it does
not readily cross the blood-brain barrier
• Glutamate is synthesized within the brain from glucose (via
KREBS cycle/α-ketoglutarate pathway in the body) and via
glutamine (from glial cells in the brain).
• Method of synthesis is through:
• Glutamate dehydrogenase reduces α-ketoglutarate to glutamate
• Transamination reactions in which an amino group is transferred
from other amino acids to α-ketoglutarate to form glutamate.
• Glutamate can be synthesized from glutamine using glutaminase
Synthesis of glutamate and GABA
and the GABA shunt. AcCoA,
acetyl coenzyme A; α-KG, α-
ketoglutarate; PLP, pyridoxal
phosphate; TCA, tricarboxylic acid.
 Glutamate cont..

• Like other neurotransmitters, glutamate is stored in

vesicles, and its release is Ca2+ -dependent.
• The excitatory action of glutamate is terminated by a
chloride-independent amino acid membrane transport
system in the neurons and astrocytes that reabsorbs
glutamate into the presynaptic membrane
• It is removed from the synaptic cleft by high-affinity
uptake systems present in nerve terminals and glial
cells.
The Synaptic Transmission
Neurotransmitters

Synthesis:

Inactivation:

Functions:

• Learning & memory astrocytes

• Motor functions

• ALS
• Excitotoxicity/PSN (Ca2+)
o CVA
o Alzheimer’s disease
43
 Other Amino Acid Neurotransmitters
ASPARTATE
• Aspartate is an excitatory
neurotransmitter.
• It is synthesized from the TCA cycle
intermediate oxaloacetate via
transamination reactions
• Aspartate synthesis uses oxaloacetate
that must be replaced through
anaplerotic reactions
• Aspartate cannot pass through the
blood-brain barrier
• Aspartate, along with glycine, opens ion
channels and is primarily in the ventral
spinal cord; it is inactivated when
reabsorbed into the presynaptic
membrane
GLYCINE
• Glycine is the major inhibitory
neurotransmitter in the spinal
cord, brain stem and retina
 Most of the glycine in neurons is
synthesized de novo within the
nerve terminal from serine by the
enzyme serine hydroxy methyl
transferase, which requires folic
acid.
 Serine, in turn, is synthesized
from the intermediate 3-
phosphoglycerate in the glycolytic
pathway.
 The action of glycine is probably
terminated via uptake by a high-
affinity transporter.
Cont..
• when released into a synaptic cleft it binds to
receptors making the postsynaptic membrane
more penetrable to Cl– ions
• This movement hyperpolarises the membrane,
creating less chance for depolarisation and
makes glycine as an inhibitory
neurotransmitter
• Glycine blocked by strychnine, which can Strychnine, pesticide

stick to the glycine receptor and prevent the

opening of the chloride ion channel, thus
stopping inhibition.
• This disinhibition and consequent spinal
hyper-excitability are the very things that
make strychnine poisonous (by suffocating or
exhausting its victims).
46
 Monoamines neurotransmitters

• Monoamines neurotransmitters regulate

 Consciousness
 Cognition
 Attention and
 Emotion

• Many disorders of your nervous system involve

abnormalities of monoamine neurotransmitters, and
many drugs that people commonly take affect these
neurotransmitters
 Catecholamine
Dopamine, norepinephrine, epinephrine, and serotonin are catecholamines
Biosynthesis
 Dopamine, norepinephrine and epinephrine are synthesized in a common
pathway from the amino acid L-tyrosine
 Tyrosine is supplied in the diet or is synthesized in the liver from the
essential amino acid phenylalanine by phenylalanine hydroxylase
 Tyrosine, a small amino acid, is transported in the neurons of
 Tyrosine hydroxylase, the key enzyme of biosynthesis, converts
phenylalanine into dihydroxyphenylalanine (DOPA).
 The enzyme DOPA decarboxylase then converts DOPA to dopamine
 The enzyme dopamine β-hydroxylase then converts dopamine to
norepinephrine
 Finally norepinephrine converted to epinephrine, in the presence of
phenylethanolamine N-methyltransferase (PMNT)
Biosynthesis of Catecholamines

49
 Dopamine
• Usually inhibitory neurotransmitter
• Dopamine plays a role in your body’s reward system, which
includes feeling pleasure, achieving heightened arousal and
learning.
• Dopamine also helps with focus, concentration, memory, sleep,
mood and motivation.
• Diseases associated with dysfunctions of the dopamine system
include Parkinson’s disease, schizophrenia, bipolar disease,
restless legs syndrome and attention deficit hyperactivity disorder
(ADHD)
• Many highly addictive drugs (cocaine, methamphetamines,
amphetamines) act directly on the dopamine system.

50
Cont..

Synthesis:

Inactivation:

51
 Epinephrine
• Usually excitatory neurotransmitter
• Epinephrine (also called adrenaline) and norepinephrine are
responsible for body’s so-called “fight-or-flight response” to
fear and stress.
• These neurotransmitters stimulate body’s response by
increasing your heart rate, breathing, blood pressure, blood
sugar and blood flow to muscles, as well as heighten
attention and focus to allow you to act or react to different
stressors.
• Too much epinephrine can lead to high blood pressure,
diabetes, heart disease and other health problems.
• As a drug, epinephrine is used to treat anaphylaxis, asthma
attacks, cardiac arrest and severe infections.
Cont..

Synthesis:

Inactivation:

53
 Norepinephrine
• Usually inhibitory neurotransmitters
• Norepinephrine (also called noradrenaline) increases blood
pressure and heart rate.
• It’s most widely known for its effects on alertness, arousal,
decision-making, attention and focus.
• Many medications (stimulants and depression medications) aim to
increase norepinephrine levels to improve focus or concentration
to treat ADHD or to modulate norepinephrine to improve
depression symptoms.
• Inactivation:
o Reuptake into synaptic terminal

o Uptake by effector cells

o Diffusion away from site.
Cont..
Synthesis:

Inactivation:

55
 Serotonin

• Serotonin is also referred to as 5-hydroxytryptamine (5-HT).

• Serotonin is synthesised from the amino acid tryptophan
• It is an inhibitory neurotransmitter
• In the central nervous system regulate
 Anger
 aggression
 Mood
 sleep patterns
 body temperature,
 pain, anxiety, sexuality, vomiting, decision-making behaviors and
appetite
• Diseases associated with serotonin imbalance include seasonal
affective disorder, anxiety, depression, fibromyalgia and chronic
pain.
Synthesis and inactivation of serotonin.
The Synaptic Transmission
Neurotransmitters

58
Serotonin receptors have defined
roles,
 5-HT1A has role in
anxiety/depression,
 5-HT1D has a role in migraine
(sumatriptan stimulates),
 5-HT2 has roles in CNS behaviors
and in cardiovascular system
(CVS)
 5-HT3 has roles in nausea and
vomiting, especially due to
chemotherapy and radiotherapy
59
Peptide neurotransmitters
Acetylcholine
This excitatory neurotransmitter in CNS and in peripheral nervous
system
•It regulating and plays a role in
Heart rate
Blood pressure and gut motility
muscle contractions
Memory
Motivation
Sexual desire
Sleep and learning

•Imbalances in acetylcholine levels are linked with Alzheimer’s

disease, seizures and muscle spasms
 Acetylcholine Synthesis

• The synthesis of
acetylcholine from acetyl
CoA and choline is
catalyzed by the enzyme
(choline acetyltransferase )

• Sources of Choline

• From the blood (eggs,

legumes)
• From the hydrolysis of
phosphatidylcholine
in membrane lipids Acetylcholine synthesis and degradation
Cont..
Synthesized as a combination
of acetyl-coenzyme A (CoA)
from Krebs cycle and choline
from food (eggs, legumes)
ACh is synthesized by enzyme
choline acetyltransferase and is
degraded by the enzyme
acetylcholinesterase

62
 Gaseous Neurotransmitters
 Nitric Oxide/NO
 Nitric oxide (NO) is a biologic messenger in a variety of physiologic
responses, including
 Vasodilation,
 Neurotransmission
 The ability of the immune system to kill tumor cells and parasites

 Is is synthesized from amino acid L- arginine by nitric-

oxide synthase
 NO synthase activates guanylate cyclase, which stimulates
the formation of cGMP from GTP
 NO is synthesized as needed and diffuses from the
cytoplasm of the postsynaptic to the presynaptic cell
63
 Nitric Oxide Vs. Classical NT

1. It is not stored in vesicles and is generated when it is needed.

2. It is not released by calcium-dependent exocytosis from a presynaptic

terminal.

3. Inactivation of NO is passive

4. It does not interact with receptors on target cells

5. NO acts as a retrograde messenger and regulates the axon terminals

presynaptic to the neuron in which it is synthesized.

64
NO as a retrograde messenger

Cell A releases a neurotransmitter,

which stimulates cell C to produce
NO. NO, being a gas, can diffuse
back and regulate cell A’s
production and release of
neurotransmitters.
NO can also diffuse to cell B, and
to stimulate cell B to produce a
different neurotransmitter to elicit
a response from cell D
Nitric Oxide (NO) Synthesis
a. Liberated in the conversion of L-arginine to citrulline
b. The enzyme nitric oxide synthase (NOS) is a complex
enzyme requiring NADPH, flavin adenine dinucleotide
(FAD), Flavin mononucleotide (FMN), and
tetrahydrobiopterin (BH4)
c. NOS is found in three major isoforms
1) Neuronal NOS (nNOS or NOS-1)
2) Macrophage or inducible NOS (iNOS or NOS-2).
3) Endothelial NOS (eNOS or NOS-3)

66
Nitric oxide (NO) synthase synthesizes the free radical nitric
oxide. FAD, flavin adenine dinucleotide; Fe-Heme, iron
hemoglobin; FMN, flavin mononucleotide
67
Synthesis:

68
Function
 iNOS is important in macrophages and neutrophils for creating
NO for the generation of free radicals, which are bactericidal or
kill invading microorganisms
 NO stimulates the influx of Ca2+ into vascular endothelial cells,
with the activation of cyclic guanosine monophosphate (cGMP)
resulting in relaxation of vascular smooth muscle (NO is also
known as endothelium-derived relaxation factor [EDRF]).
When the smooth muscle cells relax, blood vessels dilate
 NO stimulates penile erection by acting as a neurotransmitter,
stimulating smooth muscle relaxation that permits the corpus
cavernosum to fill with blood 69
Action of nitric oxide (NO)
in vasodilation

The synthesis of NO occurs in

response to a stimulator
binding to a receptor on some
cells or to a nerve impulse in
neurons. NO enters smooth
muscle cells, stimulating
guanylate cyclase to produce
cGMP, which causes smooth
muscle cell relaxation. When
the smooth muscle cells relax,
blood vessels dilate.
The Synaptic Transmission
Neurotransmitters

Summary

71
Thank you