NEUROENDOCRINE REGULATION

Lecture 5.20

Neurotransmitters: metabolism
and function

lect. Evelina Rekuvienė

LUHS Department of Biochemistry
evelina.rekuviene@lsmuni.lt
Outlines:

1. Chemical synapses
2. Types of neurotransmitters
3. Representatives of neurotransmitters: synthesis and
inactivation
 Neuron communication

80 billion nerve cells

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Types of synapses

4
 Electric and chemical signaling

 an action potential triggers the  ions flow directly between cells

presynaptic neuron to release
chemical messengers so called
neurotransmitters 5
 Chemical synapse
 a specialized junction where one part of a neuron contacts and
communicates with other neuron or target cell

 presynaptic membrane

 postsynaptic membrane

 neurotransmitters are the chemicals used to communicate neurons

with one another.
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 How can we decide which of chemicals are
transmitters?

A criterias that must be for a molecules considered as

neurotransmitters:
1. A system of compound production (enzymes, coenzymes and
substrates) are located in neurons.
2. The rate of synthesis is regulated to correspond to the rate of firing
of the neuron.
3. A compound is stored in secretory vesicles in neuron.
4. Action potential or membrane depolarization cause the release of
neurotransmitter from neural terminus.
5. Neurotransmitter is recognized by receptors of postsynaptic cells.
6. The action of the neurotransmitter is terminated through reuptake
into the presynaptic terminal, diffusion away from the synapse, or
enzymatic inactivation. 7
Exocytosis of neurotransmitter

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 Action of neurotransmitter

Acetylcholine

Glycine
K+

 The information as the change in electrochemical potential is converted into

amount and duration that neurotransmitter is present in the synaptic cleft.
 The action of neurotransmitters can be stopped by diffusion, enzymatic
degradation or reuptake system.
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 Classification of neurotransmitter by
structure

Small molecules Neuropeptides Gasotransmitters

• Endorphins • Nitric oxide

• Amino acids • Substance P • Carbon monoxide
• Monoamines • Cholecystokinin
• Insulin
• Vasopressin
• Oxytocin
• More than 40
others
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 Small molecules

Amino acids Monoamines Acetylcholine

• Glutamate Catecholamines:
• Aspartate • Dopamine
• GABA • Norepinephrine
• Glycine • Epinephrine

Indolamines:
• Serotonine
• Melatonin

Imidazolamines:
• Histamine 11
 Neurotransmitters and their receptors

Two classes of Small molecules of Peptide

neurotransmitters neurotransmitters neurotransmitters

Two classes of Ionotropic receptors Metabotropic receptors

receptors (ligand-gated ion (activates second
receptors) messenger systems)

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 Glutamate
Glutamine

 An excitatory neurotransmitter in the

CNS;
 Non-essential amino acid;
 Synthesized from glutamine using
glutaminase or from α-ketoglutarate by
glutamate dehydrogenase (GDH) or
through transamination reaction.

α-KG, α-ketoglutarate; NAD, nicotinamide adenine

dinucleotide; AA, amino acid; PLP, pyridoxal
phosphate.

[Mark’s Basic Medical Biochemistry, 5th edition, 2018;

Stobart J L , Anderson CM. Multifunctional role of astrocytes as gatekeeps of neuronal 13
energy supply. Frontiers in Cellular Neuroscience, 2013]
 Glutaminergic synapse

 Packaged to synaptic vesicles by

specific transporters
 Released during membrane
depolarization
 Released binds to postsynaptic
glutamate receptors
 Removed from the synaptic cleft
by high-affinity uptake system in
nerve terminal and glial cells.
 Metabolized to glutamine by
VGLUT- the vesicular glutamate transporter; EAAT-
enzyme glutamine synthetase
the excitatory amino acid transporter
 Glutamate-glutamine cycle
[Psychopharmacology, 2-nd edition, 2013]
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Postsynaptic receptors of glutamate

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 -amino butyric acid (GABA)

 Is the major inhibitory

neurotransmitter in the CNS.
 GABA is formed in vivo via the GABA
shunt.
Succinate
GAD
semialdehyde
 Synthesized in nervus terminal by
the decarboxylation of glutamate by
the enzyme glutamic acid
decarboxylase (GAD).
 Alteration of the GABAergic
functions results neurological and
mental disorders such as Hunting-
α-KG, α-ketoglutarate; AcCoA, acetyl coenzyme A;
PLP, pyridoxal phosphate.
ton’s chorea, Parkinson’s disease,
senile dementia, Alzheimer’s
disease, and schizophrenia.
[Mark’s Basic Medical Biochemistry, 5th edition, 2018] 16
 GABA shunt
 GABAA, GABAB
 GABA is taken by specific GABA
transporters in to glial cells.
 Converted to glutamate by a
mitochondrial enzyme GABA
transaminase.
 Glutamate is then converted to
glutamine and transported out of the
glial cells to neurons.
 Glial cells lack glutamic acid
decarboxylase and cannot synthesize
GABA GABA.
transaminase

 Valproic acid inhibits enzymatic degradation of GABA in synaptic cleft

 Barbiturates act as agonists on postsynaptic GABA receptors 17
 Glycine
 An amino acid
 An inhibitory neurotransmitter
 Glycinergic synapse are abundant in
spinal cord and brain stem motor
neurons
 Also found in higher brain regions
including hippocampus
 As cotransmitter at glutaminergic
synapses for activation
of ionotropic channels.

Strychnine
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 Acetylcholine
• An excitatory neurotransmitter;
• In both the PNS and the CNS:
• motor neurons, basal ganglia,
• the preganglionic sympathetic and parasympathetic
neuron of ANS
within the CNS – neurotransmitter &
neuromodulator
• Damage to the cholinergic neurons of
the CNS is associated with Alzheimer
disease.

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Cengage Learning 2016
The life cycle of acetylcholine
Glucose oxidation

Is synthesized from acetyl

coenzyme A and choline by the
enzyme choline acetyltransferase
in the cytosol of presynaptic
terminal.

Acetylcholinesterase breaks
down acetylcholine in synaptic
cleft into choline and acetic
acid.
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Cholinergic synapse

 the transport of choline into the

neuron is the rate-limiting step in
Ach synthesis;
 Ach breakdown goes very
quickly;
 Much of the resulting choline is
taken up by the cholinergic axon
terminal and reused for ACh
synthesis.

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 Acetylcholine receptors

Nicotinic receptors Muscarinic receptors

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Biogenic amines neurotransmitters

Byrne, J. H. (ed.), Neuroscience Online: An Electronic 23

Textbook for the Neurosciences, 1997.
Catecholamines neurotransmitters
Dopamine:
• involves in reward, motivation and additions;
• several types of addictive drugs increase
dopamine levels in the brain;
• plays important role in the coordination of body
movements - Parkinson's disease.
Noradrenaline:
• involves in the body's fight or flight response -
helps mobilize the body and brain to take
action in times of danger or stress.
Adrenaline:
• is a stress hormone and functions as a
neurotransmitter in the brain.
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 Synthesis of catecholamines

• Are synthesized in a common

pathway from the amino acid L-
tyrosine;.
Pyridoxal phosphate
• The product depends on
presence/absence of required
enzymes in neuron.
Dopaminergic neurons
Vit.C • L-dopa is produced by the
(in synaptic vesicles) enzyme tyrosine hydroxylase
(TH),
• Coenzymes Vit. B6 and C are
Noradrenergic neurons
required.
(in cytosol)

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Adrenergic neurons
 Release and reuptake of catecholamines
 Dopaminergic receptors: D1, D2,
D3 and etc.
 Adrenergic receptors: α1, α2, β1,
β2.
 The actions in the synaptic cleft are
terminated by selective uptake back
into the axon terminal via Na-
dependent transporters;
 Inside the axon terminal they may
be reloaded into synaptic vesicles
for reuse, or may be enzymatically
destroyed by the action of enzymes.
β-blockers
Cocaine, amphetamine 26
 Enzymatically inactivation of
catecholamines

Monoamine oxidase (MAO) or

catechol O-methyltransferase (COMT)
+ NH4+

SAM
O2

excreted in the urine

Monoamine oxidase inhibitors (MAOIs) 27
 Indolamines neurotransmitter

(an inhibitory neuromediator)

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 Synthesis of serotonin and
melatonin
Tryptophan hydroxylase

Hydroxyindoleacetic acid (5-HIAA)

5-hydroxyTrp
Pyridoxal Inactivation by monoamine
phosphate Aromatic amino acid
decarboxylase
oxidase (MAO) or catechol O-
methyltransferase (COMT)

(5-HT) Serotonin 5HT1A, 5HT1B, 5HT2, 5HT3

SAM
Acetyl-CoA Methyltransferase
Acetyltransferase
Selective inhibitors of
serotonin reuptake (SSRIs)
Melatonin
Pineal gland (endocrine) 29
 Histamine
 An excitatory neurotransmitter in the CNS, especially
hypothalamus.
 Produced by mast cells and certains neuronal fibers.
 Synthesized from histidine in a single enzymatic step:
Histidine decarboxylase
Pyridoxal phosphate
OOH
Histidine CO2 Histamine
H1, H2, H3, H4, H-gated Cl- channel
receptors
Inactivation: Brain
Peripheral tissues
Histamine methyl transferase
Diamine oxidase (DAO)
Monoamine oxidase (MAO)
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N-methylimidazolylacetate Imidazolylacetate
view an online animation that accompanies Neuroscience, 5th edition, chapter 6

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