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3 | Neurotransmitters
Subject:
Title:
Lecturer:
Batch/section:
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
(+)stimulated/
depolarized
Released into the synaptic
cleft (R)
Postsynaptic
neuron
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Read
info:
http://neuroscience.uth.tmc.edu/s1/chapter11.html#mr
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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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
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.
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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D. Biologic Effects
Dopamine
(dopaminergic areaphysiologic
function)
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
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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o
o
A. SEROTONIN
Vasoconstrictor
Stimulates smooth muscle
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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)
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
Synthesis
Histidine (precursor)
Histidine is decarboxylized by the enzyme
histidine decarboxylase (requires pyridoxal
phosphate) to histamine
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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
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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E. ASPARTATE
Synthesis
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).
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
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