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BIOCHEMISTRY 1.

3 | Neurotransmitters

Subject:
Title:
Lecturer:
Batch/section:

UERMMMCI College of Medicine


Biochemistry
June 19, 2014
Date:
(1.3) Biochemistry of Neurotransmitters
Dr. Catherine L. Co-Reportoso
st
2018A
Sem/ A.Y.:
1 /A.Y. 2014-2015

Transcribers: Arce, J., Arquiza, A., Arriba, H., Avenir, M., Azarraga, C., Balberia, J.
Trans Subject head: Evangelista, A. (9369390879/alanaevangelista@gmail.com)

OUTLINE
I. Neurotransmission
II. Acetylcholine
A. Synthesis and Storage
B. Release
C. Classes of Acetylcholine Receptors
D. Degradation
E. Biologic Effects
F. Clinical Application
III. Catecholamines
A. Synthesis
B. Storage
C. Release
D. Biologic Effects
E. Reuptake
F. Inactivation and Degradation
G. Degradation of NE/E
H. Clinical Application
IV. Amino Acids and Derivatives
A. Serotonin
B. Histamine
C. Glutamate
D. Glycine
E. Aspartate
F. GABA
G. Nitric oxide
V. Summary tables

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OBJECTIVES
Define neurotransmission and its basic
components
Identify the different groups of neurotransmitters
Discuss the metabolism of each neurotransmitter
as to
o precursor
o biochemical pathway
o synthesis and storage
o release
o degradation
Briefly discuss the physiologic functions/effects of
each neurotransmitter
Explain the biochemical basis of some
neurotransmitters
o Myasthenia Gravis

o
o
o
o

Parkinsons Disease
Depression
Carcinoid Syndrome
Allergic Reaction

I. NEUROTRANSMISSION
essential for the process of communication
between two neurons
Presynaptic
neuron

Chemicals are packaged into


synaptic vesicle (S)

(+)stimulated/
depolarized
Released into the synaptic
cleft (R)

Postsynaptic
neuron

Bind to specific receptors


biologic effects (B)

*Reuptake (all NT except Ach)


*Enzymatic inactivation (I)

Steps involved in synaptic transmission


(S-R-B-I)
1. S-synthesis and storage
2. R-release
3. B-binding
4. I-inactivation
Synapse the junction between 2 cells where the
impulse is transmitted from one cell to another
o 2 types of synapses
Electrical less common; gap junctions
link 2 cells and directly transmit changes
in membrane potential between cells

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Chemical most common type of


synapse; NTs are released from a
presynaptic neuron, and dock with
receptor proteins on the postsynaptic
neuron
Neurotransmitter - endogenous chemicals which
relay, amplify, and modulate signals between a
neuron and another cell
Different groups of NTs
o Cholinergic agent (Ach)
o Catecholamines (dopamine, norepinephrine,
epinephrine)
o Amino acids and its derivatives (serotonin,
histamine, glutamate, aspartate, glycine,
GABA, nitric oxide)

Read

II. ACETYLCHOLINE (Ach)


for
more

info:

http://neuroscience.uth.tmc.edu/s1/chapter11.html#mr

C. Classes of Acetylcholine Receptors


Nicotinic Acetylcholine Receptor (AchR)
o Ligand-gated ion channel (ionotropic
receptor)
o Ach binds to each of the 2 alpha subunits of
the receptor
o Conformational change will then occur
o There is an influx of Na+ ions resulting to
depolarization of postsynaptic membrane

A. Synthesis and Storage


Acetylcholine is synthesized in the cytosol of
nerve terminals
An acetyl group from acetyl CoA transferred to
choline
o Catalyst: Choline Acetyl Transferase
Stored inside the synaptic vesicle via Vesicular
acetylcholine transporter (VAChT)
o With the use of VATPase Proton Pump
o H+ goes out of the synaptic vesicle in
exchange for the Ach

Resting level synaptotagmin1 (a calcium


protein) is bound to Q SNARE syntaxin,
preventing the vesicle fusion
o If there is an influx of extracellular Calcium,
synaptotagmin1 is bound to calcium and
syntaxin is released, thus vesicle fusion is
permitted.
(Binding) Nicotinic AchR
o the endocytic vesicle loses their clathrin coat
and are filled with Ach by the H+-Ach antiport
o it is then translocated back to the active zone
o the docked vesicles are held in the active
zone by synapsin1
o

Muscarinic Acetylcholine Receptor


o G-Protein gated (metabotropic receptor)
o Ach binds to the receptor mediated by the GProtein
o Alpha subunit releases bound GDP and
binds itself to GTP
o Alpha subunit detaches from the G-protein
complex and will interact with the effector
o K+ channel opens adenylyl cyclise is
inactivated activation of some other
enzymes

B. Release
Neuron is stimulated
2+
o Voltage gated ion channel of Ca opens
2+
o Extracellular Ca go in
Exocytosis of synaptic vesicles is stimulated

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G. Clinical Application: Myasthenia Gravis

D. Degradation
No reuptake occurs
Acetylcholinesterase
o Located in the post synaptic membrane
o Facilitates enzymatic inactivation of Ach
o Hydrolyzes Ach to form acetate and choline
o Acetate diffuses away, while choline is
transported back to the presynaptic neuron
by a choline carrier

Myasthenia Gravis an autoimmune disorder

E. Biologic effects
Peripheral Nervous System
o Acetylcholine is found in the NMJ
Neuromuscular junction
o The AchR that is found here are exclusively
nicotinic
o Main Function: Stimulation of muscle fiber =
contraction
Central Nervous System
o Acetylcholine is found in the interneurons
o There is a cholinergic projection from the
nucleus basalis Myenert to the forebrain
neocortex that is associated with limbic
structures
o AchR in the CNS are nicotinic and muscarinic
o The degradation of this pathway is often
associated with Alzheimers disease.

Antibodies that circulate the body bind to AchR at


the neuromuscular junction (NMJ)
Result: Acetylcholine of post synaptic receptor in
the NMJ is blocked no depolarization and no
muscle contraction will take place
There is an inability to form a coupled reaction
Symptom: Drooping of both eyelids, extensive
muscle weakness
Medications
o Immunosuppressive
drugs:
prednisone,
cyclosporine, mycophenolate mofetil and
azathioprine Controls antibodies
o Acetylcholinesterase inhibitors: neostigmine
and pyridostigmine slows down
acetylcholinesterase giving Ach a longer time
to stimulate receptors
III. CATECHOLAMINES
Examples of catecholamines are: epinephrine
(adrenaline), norepinephrine (noradrenaline),
dopamine
Contains catechol, composed of a phenyl ring
with two adjacent hydroxyl side groups (found in
all catecholamines)

A. Synthesis of Catecholamines
1. Phenylalanine from the liver is converted into
tyrosine by phenylalanine hydroxylase. Tyrosine
can also be supplied by the diet.
2. Hydroxylation of tyrosine by tyrosine hydroxylase
dihydroxyphenylalanine (DOPA).
3. The decarboxylation of DOPA by pyridoxal
phosphate (DOPA decarboxylase) dopamine
4. Dopamine is now stored in the synaptic vesicle
where dopamine -hydroxylase (DBH; this

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enzyme is only present within these storage


vesicles) norepinephrine.
5. Norepinephrine
is
now
methylated
by
phenylethanolamine N-methyltransferase
epinephrine
B. Storage of Catecholamines
Transported into the vesicles via VMAT2 (vesicle
monoamine transporter 2). Vesicular ATPase (VATPase) pumps protons into the vesicle to be
exchanged for positively charged catecholamine.
Serotonin and histamine can also be transported
by VMAT2.
C. Release of Catecholamines
When an action potential hits the nerve terminal,
Ca2+ channels open Ca2+ enters (the vesicles
fuse with neuronal membrane) which then
triggers
the
release
of
the
content
(neurotransmitter, ATP, chromogranins etc.) into
the synaptic vesicle. Ready for exocytosis.
They now diffuse across the synaptic cleft they
produce their specific response.

Synthesis of epinephrine from tyrosine

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D. Biologic Effects
Dopamine
(dopaminergic areaphysiologic
function)

Substantia nigra in the basal


ganglia Voluntary motor
control

Ventral
tegmental
area
(limbic part of striatum)
Motivation

Arcuate
nucleus
and
periventricular nucleus of the
hypothalamus
(pituitary
gland) Regulates the
release of certain hormones

Norepinephrine/epinephrine

Important for attention,


emotion,
sleeping,
dreaming and learning
Responsible for the fight
or flight response which
in turn activates the
sympathetic
nervous
system by:
o Increasing heart rate
o Release
stored
energy from fat
o Prepares muscles for
action

E. Reuptake of Catecholamine

F.
Inactivation
and
Degradation
of
Catecholamines
Reuptake back into the presynaptic terminal and
diffusion away from the synapse terminates the
action of catecholamines.
Degradative enzymes are present in both the
presynaptic terminal and in adjust cells.
Monoamine oxidase (MAO; intracellular
responsible for the degradation of dopamine in
the presynaptic neuron).
Catechol-o-methyltransferase
(COMT;
extracellular responsible for the degradation of
dopamine if it is not transported back into the
presynaptic neuron)
Homovanillic acid is formed when
o Dopamine is oxidized by MAO
dihydroxyphenylacetic acid which is when
acted upon by COMT.

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Dopamine is acted upon by COMT and then


oxidized by MAO to form the same product

o
o

Dopamine Analogue (Levodopa) The


administration of L-Dopa (The form that can
cross the blood brain barrier) temporarily
diminishes the motor symptoms
Dopamine Agonists
Apomorphine, pramipexole, ropinirole,
roligotine
MAO Inhibitors
Selegiline, rasagiline
MAO breaks down dopamine secreted by
the dopaminergic neurons, thus the
inhibitors will allow the level of dopamine
in the basal ganglia to increase
help increase L-dopa in the striatum
IV. AMINO ACIDS AND DERIVATIVES
A. Serotonin
B. Histamine
C. Glutamate
D. Glycine
E. Aspartate
F. GABA (gamma-aminobutyric acid)
G. Nitric oxide

G. Degradation of Norepinephrine / Epinephrine


MAO (oxidative deanimation) and COMT (Omethylation) act on norepinephrine / epinephrine
to form vanillyl mandelic acid

A. SEROTONIN
Vasoconstrictor
Stimulates smooth muscle

H. Clinical Application: Parkinsons Disease


Degradation of dopaminergic neurons in the
substantia nigra of the midbrain
The patient exhibit loss of voluntary motor control
and trembling-like movements from their arms
and legs.
Common medications given:

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Synthesis of Serotonin
Tryptophan precursor to serotonin
1. Tryptophan taken up by serotonergic neurons in
restricted brain areas such as the raphe nucleus
2. Once it enters the neurons, tryptophan
hydroxylase adds the hydroxyl group and
produces 5-hydroxytryptophan (5-HT)
3. 5-HT is further decarboxylated by dopa
decarboxylase to produce serotonin
4. Serotonin is then stored in synaptic vesicles and
docked at the nerve terminals, where it awaits an
action potential
5. Release of serotonin into the synaptic cleft
activates serotonergic receptors in the post
synaptic neurons
Synthesis of Melatonin
Serotonin (precursor)
1. Acetylation of the amine group by N-acetyl
transferase leading to N-acetyl serotonin
2. Methylation of the OH group by 5-hydroxyindoleO-methytransferase catalyzing the transfer of a
methyl group by S-adenosylmethionin to obtain
acetyl-5 methoxytryptamine or melatonin
Inactivation and Degradation of Serotonin
1. Serotonin is inactivated by MAO (monoamine
oxidase)
2. Oxidative deamination by MAO 5
hydroxyindole acetaldehyde oxidized into 5
hydroxyindole acetic acid (found in uine) by
aldehyde dehydrogenase
Storage of Serotonin
Vesicular ATPase proton pump via vesicular
monoamine transporter 2 (VMAT 2)

Implicated in jet lag

Clinical Application
Depression - decreased level of serotonin
Symptoms:
o Lack of energy and motivation
o Less alert than usual; lack of sleep
o Low memory retention
o Loss of interest; low self-esteem
Medications
o Selective Serotonin reuptake inhibitors
(SSRIs)
Prozac
Block the reuptake of serotonin into
the presynaptic Neuron
o Tricyclic antidepressant
Decrease serotonin reuptake and
subsequent rise in serotonin levels in
the synapse
Carcinoid syndrome
Increase in serotonin (overproduction from the
tumor)
Occurs in 5% with carcinoid tumor in GI tract
(midgut)
Carcinoid tumor malignant neuroendocrine
tumor of the SI, producing serotonin increase
amount of serotonin secretion
Symptoms:
o Flushing
o Diarrhea
o Heart failure: serotonin induced fibrosis of the
valvular endocardium

B. HISTAMINE
Produced by mast cells and by certain neuronal
fibers within the brain
Potent local mediator of allergic reactions

Reuptake: Serotonin Transporter (SERT)

Biologic effects of Serotonin


GIT (enterochromaffin cells) 80% regulates
intestinal movements
Brain appetite, sexual behavior, and mood
control
Low level depression
Extremely high level mania, reduced appetite
and sexual behavior
Pineal gland regulation of sleep
Blood platelets vasoconstrictor

Synthesis
Histidine (precursor)
Histidine is decarboxylized by the enzyme
histidine decarboxylase (requires pyridoxal
phosphate) to histamine

Biologic effects of Melatonin


Produced in the pineal gland
Controls sleep-wake cycle (circadian rhythm)
Conveys information about light-dark cycles of
the body
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Release
Depolariztion of nerve terminals activation of
release of histamine by voltage -dependent and
calcium-dependent mechanism activate both
post synaptic and presynaptic receptors
Storage
Vesicular ATPase proton pump via vesicular
monoamine transporter 2 (VMAT 2)
Biologic Effects
Chemical messenger that mediates a wide range
of cellular responses e.g. immunologic responses
Location

Physiologic
effects

Disease

H1
Lung, Brain,
vessels
Contraction
of
smooth
muscle,
sleep-wake
regulation
Allergic
reaction

H2
Heart,
brain,
stomach
Gastric
acid
secretion

H3
Neurons

H4
Mast
cells,
eosinophils

Sleep, food
intake

Chemotaxis

Gastric
ulcer

Cognitive
impairment

Inflammation,
immune
response

Inactivation and degradation of Histamine


Histamine, unlike other neurotransmitters, is not
recycled into the presynaptic terminal.
Astrocytes, however, have a specific high-affinity
uptake system for histamine and may be the
major sites of the inactivation and degradation of
histamine.
Patients with allergic reaction cannot degrade
histamine because they have low activity of
diamineoxidase.
1. 1st
step:
methylation.
Histamine
methyltransferase transfers a methyl group
from S-adenosylmethionine (SAM) to a
nitrogen ring of histamine to form
methylhistamine
2. 2nd step: oxidation. Oxidation by MAO-B,
followed by an additional oxidation step. In
the peripheral tissues, histamine undergoes
deamination by diamine oxidase followed by
oxidation to a carboxylic acid.
Clinical Application
Allergic reaction
Release of histamine and other inflammatory
agents
Symptoms:
o Localized allergic reaction
o Runny nose
o Watery eyes
o Constriction of bronchi
o Tissue swelling
Medications:
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o
o

Diphenhydramine
Chlorpheniramine

C. GLUTAMATE
Synthesis
Synthesized via glutamine and glucose
o Deamination of glutamine
o The intermediate alpha ketoglutarate ( KG)
from glucose metabolism (via TCA pathway)
can be transformed into glutamate by
Dehydrogenation transfer of free
ammonia to KG to form glutamate
Transamination ammonia/amino group
from any amino amino acid to form
glutamate
Storage and Release
Glutamate is stored in the synaptic vesicle via
Vesicular Glutamate Transporter/VGluT, and
subsequently released by exocytosis.
Receptors
Release is Ca2+ dependent
2 kinds:
Inotropic - ligand-gated nonselective cation
channels which allow the flow of K+, Na+ and
sometimes Ca2+ in response to glutamate
binding.
o N-methyl-D-aspartate (NMDA) receptors
o Non-NMDA receptors
-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA)
Kainate receptors
Metabotropic - share a common molecular
morphology with other G proteinlinked
metabotropic receptors (mGluR), located in
glial cells
Reuptake and Degradation of Glutamate
o Nerve terminals and glial cells reuptake the
glutamate released from the nerve terminals. In
the glia, glutamate is converted into glutamine by
glutamine synthetase.
o Glutamine is inactive in a sense that it cannot
activate glutamate receptors
o It is then released from the glial cell into the
extracellular fluid where nerve terminals take up
glutamine (glutamine glutamate; glutamateglutamine cycle)
Biologic Effect
Functions as major excitatory NT within the CNS,
leading to depolarization of neurons
Glutamate plays a role in learning and memory
processes, as well as motor function

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Amyotrophic lateral sclerosis (ALS)/Lou Gehrigs


disease - characterized by degeneration of the
motor neurons in the anterior horn of the spinal
cord, brainstem, and cerebral cortex.
Excitotoxicity neuronal death by prolonged
stimulation of neurons by excitatory amino acids
Excess glutamate can overstimulate the brain
and cause seizures

E. ASPARTATE
Synthesis

transamination reaction catalyzed by aspartate


aminotransferase, AST

D. GLYCINE
Synthesis & Storage
Reaction
is
catalyzed
by
serine
hydroxymethyltransferase (SHMT)
Transfer of the hydroxymethyl group from
serinetetrahydrofolate (THF), producing glycine.
Stored in neuronal synaptic vesicles by vesicular
inhibitory amino acid transmitter (VIAAT).

can also be derived from asparagine through the


action of asparaginase

Reuptake
Released glycine is taken up by neurons by an
active sodium-dependent mechanism involving
specific membrane transporters (glycine
transporter 2).
Degradation
Three pathways of degradation for glycine
Predominant: the glycine cleavage enzyme
catabolizes glycine to carbon dioxide, ammonia
and a one-carbon fragment in the form of a
derivative tetrahydrofolate (THF) called N5, N10methylene THF (glycine+THF+NAD+ N5,N10methylene THF + NADH+CO2+NH4)
Reversal of glycine biosynthesis from serine with
serine hydroxymethyl transferase. The resulting
serine is then converted to pyruvate by serine
dehydratase (2 steps)
Glycine serine (serine OH-CH3
transferase)
Serinepyruvate (serine dehydratase)
Glycine is converted to glyoxylate by D-amino
acid oxidase
Glycineglyoxylate (aa oxidase)
Glyoxylateoxalate (lactate DH)
Biologic Effect
Most important inhibitory neurotransmitter in the
spinal cord, lower brainstem, and retina
Function as coagonist at the NMDA glutamate
receptorglycine promotes the actions of
glutamateglycine serves both inhibitory and
excitatory functions within the CNS

Receptors
Inotropic (same with glutamate):
o N-methyl-d-aspartate (NMDA)
o -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA)
o Kainite
Biologic effect
Major excitatory NT in the spinal cord
Degradation of Aspartate

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F. GABA
AKA gamma-aminobutyric acid
major inhibitory neurotransmitter in the brain
(central nervous system)
prevents over-excitation

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Synthesis
synthesized by decarboxylation of glutamate by
the enzyme glutamic acid decarboxylase

V. SUMMARY TABLES

Storage
Vesicular Inhibitory Amino Acid Transporter
(VIAAT)
Vesicular GABA transporter (VGAT)
Release and Binding
GABA is released into the presynaptic cleft after
depolarization
2 receptors:
o GABA A - ligand-gated ion channels
o GABA B - G protein-coupled receptors
Inactivation/Degradation
GABA is converted back to glutamate via GABA
shunt (Catalyzed by enzyme GABA-T, or oxoglutarate transaminase in the presence of ketoglutarate to form 2 molecules Glutamate &
Succinic semialdehyde (SSA))

G. NITRIC OXIDE
Relaxation of smooth muscles

Nitric oxide
synthase

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References
http://flipper.diff.org/app/pathways/info/4602
http://what-when-how.com/neuroscience/neurotransmitters-the-neuron-part-2/
http://themedicalbiochemistrypage.org/amino-acid-metabolism.php#glycinem
http://nba.uth.tmc.edu/neuroscience/m/s1/chapter13.html
th

Biochemistry, 4 ed by Garrett, pp 1046-1056


nd
Marks Basic Medical Biochemistry 2 ed, pp 888-899
th
Biochemistry, 4 ed by Voet and Voet, pp 779-785

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