Biochemistry of

neurotransmitters
Dr Shivananda Baliga
Professor of Biochemistry
AUA
Office: GC 06
Phone: 1-268-484-8900 extn 1068
email: sbaliga@auamed.net
Learning Objectives:
• Goal 33: Introduction to nervous system: understand the
synthesis and degradation of neurotransmitters
• 33a. Given examples of neurotransmitters, classify them
according to their biochemical nature
• 33b. Given an example of biosynthesis and degradation of
common neurotransmitter, distinguish the reaction pathways
Reference:
Baynes, J. W. & Dominiczak, M.H. Medical Biochemistry, 4th ed.
2014, Saunders Elsevier, Chapter 41.1, Pages 551 - 563
Neurotransmitters:
• Definition: Molecules that act as chemical
signals between nerve cells
• Neurotransmitter,
 Synthesized within the neuron
 Stored in the nerve terminals (in
synaptic vesicles)
 Released in response to an appropriate
stimulus
 Able to bind to a receptor on post-
synaptic membrane
 Locally inactivated & its action
terminated
Classification of neurotransmitters based on chemical nature:
1) Amines:
- Acetylcholine (ACh)
- Dopamine, epinephrine, norepinephrine (catecholamines)
- Serotonin
- Histamine
2) Amino acids:
- Glutamate, aspartate
- Glycine, γ-Amino butyric acid (GABA)
3) Purines: → ATP, adenosine
4) Gases: → Nitric oxide
5) Neuropeptides:
- Opioid peptides (endorphins)
- Vasoactive Intestinal peptide (VIP)
 Choline Choline
Na+ Acetyl Choline acetyl
Na+ CoA transferase
CoA
Axon
Acetylcholine (Ach) terminal

Ach
Ach Synaptic vesicle
Ach Ca++ Ca++
Choline
Release by exocytosis
H2O Ach Presynaptic membrane
Acetate Ach Ach
Acetylcholine
esterase Ach Postsynaptic membrane
Acetylcholine synthesis
& degradation:
Ach receptor
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MYASTHENIA GRAVIS
• Autoantibodies formed against ACh receptors in
neuromuscular junctions
• Bind to receptors & block access of ACh to them
• Damaged receptors endocytosed → reduce
receptor number
• Inefficient transmission of nerve impulses to muscle
• Muscles supplied by cranial nerves affected
• Weakness of voluntary muscles (eg: muscles
controlling movement of eyelids, chewing,
speaking)
• Treated with drugs that inhibit acetylcholine
esterase → increase concentration of ACh in the
synaptic cleft → compensates for the reduced
number of receptors
 Catecholamines: Dopamine, norepinephrine, epinephrine
All synthesized from tyrosine
Dopamine & norepinephrine → neurotransmitters
Epinephrine → mainly as hormone → ‘fight or flight’ response

From diet Tyrosine Phenylalanine

Tetrahydrobiopterin + O2 Tyrosine hydroxylase

Dihydrobiopterin + H2O
Dihydroxy phenylalanine (DOPA)
CO2 Aromatic a.a decarboxylase (PLP)
Dopamine
• Inherited defects in tyrosine hydroxylase  dopamine deficiency in brain.
(progressive gait disorder & infantile parkinsonism)
• 5 major classes of dopamine receptors (D1 – D5) are
known
• Reuptake of dopamine occurs with the help of a
transporter in the presynaptic membrane
• Recycled dopamine can be incorporated into
synaptic vesicles and reused
Degradation of dopamine:
• Degradation of dopamine can occur in the synaptic
cleft or following reuptake in the presynaptic
terminal
• Dopamine is degraded by monoamine oxidase
(MAO) and catechol-O-methyl transferase (COMT)
• Degradation product is homovanillic acid

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Parkinson’s disease:
• Characterized by decreased dopamine level
• Tremor, slowness of movement,
• Rigidity, postural instability
Degeneration of Decreased dopamine level
dopaminergic neurons

Increased Ach/dopamine ratio

Imbalance leads to disorders of movement

 Synthesis of norepinephrine Tyrosine
& epinephrine
Dopa

Dopamine
Ascorbate + O2
Dopamine  hydroxylase Cu++

Dehydroascorbate + H2O
Norepinephrine
S-adenosyl methionine (SAM)
Phenylethanolamine N-methyl
transferase (PNMT) S-adenosyl homocysteine (SAH)

Epinephrine 10
Degradation of catecholamines
Epinephrine
SAM MAO
COMT
SAH Dihydroxymandelic acid
Metanephrine
COMT SAM
MAO
SAH

Vanillylmandelic acid (VMA)

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 Norepinephrine
SAM
COMT MAO
SAH
Normetanephrine Dihydroxymandelic acid
COMT
SAM
MAO
SAH
Vanillylmandelic acid (VMA)

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Pheochromocytoma:
Rare tumor of adrenal medulla

Secrete high levels of both epinephrine & norepinephrine

 plasma levels of catecholamines

Causes hypertension,  heart rate, may lead to stroke or heart failure

 degradation of catecholamines

USED AS
 urinary excretion of VMA & metanephrines DIAGNOSTIC TEST
 Serotonin synthesis & degradation
Tryptophan

Tetrahydrobiopterin + O2 Tryptophan hydroxylase

Dihydrobiopterin + H2O
5-hydroxytryptophan
Aromatic a.a decarboxylase
CO2
5-hydroxytryptamine (5-HT;serotonin)
MAO

5-hydroxyindole acetic acid

(5-HIAA; excreted in urine) 14
• Serotonin is produced by cells in GI tract and neurons in CNS
• Acts as vasoconstrictor
• Involved in pain perception; regulation of sleep, appetite, mood, anger
• Some anti-depressants act by inhibiting serotonin breakdown or
reuptake
Carcinoid syndrome:
• Serotonin producing tumors arising from enterochromaffin cells of GI
tract, may metastasize to the liver or lungs
• Increased plasma level of serotonin
• Attacks of flushing,  heart rate, abdominal pain & diarrhea
• Increased urinary excretion of 5-HIAA (diagnostic test)

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Glutamate (Glu):
• Excitatory neurotransmitter in CNS
• Widely used, responsible for 75% of excitatory transmission in brain
• Most plentiful amino acid in CNS
Distribution: cerebral cortex, brain stem
• Many classes of glutamate receptors
• NMDA receptor (named after its agonist, N-methyl D-aspartate)
Glutamate excitotoxicity:
• Extracellular glu is  after trauma, stroke, severe convulsions (maybe
due to release of glu from damaged cells or damage to glu uptake
mechanisms)
• Excess glutamate is toxic to nerve cells
• Activation of NMDA receptors by glutamate allows Ca2+ entry
into cells activation of various proteases → initiation of
apoptosis
• Activation of NMDA receptors may also  production of
NO; may be toxic to cells
-aminobutyric acid (GABA):
• GABA is the major inhibitory neurotransmitter in CNS
• GABA receptor agonists are used to treat anxiety (eg:
diazepam)

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-aminobutyric acid (GABA)
Glutamate
Glutamate decarboxylase
CO2 (PLP)

GABA
-ketoglutarate
GABA-Glutamate
transaminase
Glutamate
Succinate semialdehyde
NAD+, H2O
S.S dehydrogenase
NADH+H+
Succinate
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Glycine:
• Is an inhibitory neurotransmitter in spinal cord, brainstem & retina
• Is a co-agonist along with glutamate for NMDA receptors
• Can be synthesized from serine; from CO2 & NH3

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