Discovery of Neurotransmitters

• Otto Loewi, an Austrian scientist, discovered

the first neurotransmitter in 1921.
• He used two frog hearts.
• One heart was still connected to the vagus
nerve.
• Heart #1 was placed in a chamber that was
filled with saline.
• This chamber was connected to a second
chamber that contained heart #2.
• Fluid from chamber #1 was allowed to flow
into chamber #2.
NEUROTRANSMITER
 pengertian
• Bahan kimia dikeluarkan oleh vesicle synaptic,
bergerak maju ke celah sinapsis, berpengaruh pd
neuron sebelahnya
• Vesicle synaptic: kantung kecil di terminal button,
memroduksi bahan kimia
A
C JENIS & FUNGSI
E
T  Ach, dibebaskan otot skeletal,
Y eksitatoris & inhibitoris
L  Tdp di ganglion sistem saraf, organ target:
C sistem saraf otonom parasimpatik,
H otak
O  Berperan pd gugahan, atensi, memori,
L motivasi
I  Ach kurang: gg Alzheimer, gangguan
N memori & bahasa
E
 Loewi’s Results
• Electrical stimulation of the vagus nerve
attached to heart #1 caused heart #1 to slow
down.
• After a delay, heart #2 also slowed down.
• Loewi hypothesized that electrical stimulation
of the vagus nerve released a chemical into
the fluid of chamber #1 that flowed into
chamber #2.
• He called this chemical "Vagusstoff".
• We now know this chemical as the
neurotransmitter acetylcholine.
Otto Loewi’s Experiment
 What is a Neurotransmitter?

• A substance that is released at a synapse

by a neuron and that effects another cell,
either a neuron or an effector organ, in a
specialized manner
• This seems clear, but application becomes
fuzzy
 DEFINITION:
Neurotransmitters are the
chemical substances
which are responsible for
transmission
of an impulse through a
synapse.

Schematic diagram of synapse

CRITERIA: 50 substance are
there

 Synthesized by pre-synaptic neurons with the help

of synthesizing enzyme and stored in vesicles at
axon terminal.
 Stimulation of nerve cause release of transmitters.
 Travels between pre to post-synpatic membrane.
 Associated with an enzyme system(inactivation).
 Mimic the effects of nerve stimulation outside.
 Drugs which modifies nerve stimulation also
modifies transmitter action the similar way.
 Neurotransmitter Criteria
• Chemical messengers must meet 4 criteria to be
considered transmitters:
– It is synthesized by a neuron.
– It is present in the presynaptic terminal and is
released in amounts sufficient to exert a
defined action on a postsynaptic neuron or
effector organ.
– When given as a drug, it mimics the action of
naturally occurring transmitter in the body
exactly.
– A specific mechanism exists for removing it.
 Pengertian Neurotransmiter
Neurotransmiter merupakan senyawa kimia
pembawa pesan yang meneruskan informasi elektrik
dari sebuah neuron ke neuron lain atau sel efektor.
Sifat neurotransmiter adalah sebagai berikut:
Disintesis di neuron presinaps
Disimpan di vesikel dalam neuron presinaps
Dilepaskan dari neuron di bawah kondisi fisiologis
Segera dipindahkan dari sinaps melalui uptake atau
degradasi
Berikatan dengan reseptor menghasilkan respon
biologis.
 Neuromediators or neurohormones:

Neuromodulators:
Neuromodulators:

Eg: VIP,somatostatin,ckk,substance P etc

 Cara Kerja Neurotransmitter
• Proses neurotransmitter berawal dari neuron menyintesis zat kimia yang
akanberfungsi sebagai neurotransmitter. Kemudian neuron menyintesis
neurotransmitter yangberukuran lebih kecil pada ujung-ujung akson dan
menyintesis neurotransmitter yangberukuran lebih besar (peptida) pada
badan sel. Selanjutnya neuron mentransportasineurotransmitter peptida
kearah ujung-ujung akson (Neuron tidak
mentransportasikanneurotransmitter yang berukuran kecil karena ujung-
ujung akson adalah tempatpembuatannya). Potensial aksi berkonduksi
disepanjang akson. Potensial aksi padaterminal postsinaptik
meyebabkan ion kalsium dapat memasuki neuron. Ion
kalsiummelepaskan neurotransmitter dari terminal postsinaptik ke celah
sinaptik
• Molekulneurotransmitter yang telah dilepaskan, berdifusi lalu melekat
dengan reseptorsehinggamengubah aktifitas neuron postsinaptik.
Selanjutnya, neurotrasmiter melepaskandiri dari reseptor.
Neurotrasmitter dapat diubah menjadi zat kimia yang tidak
aktif tergantung pada zat kimia penyusunnya. Molekul neurotransmitter
dapat dibawa kembalike neuron prasimatik untuk didaur ulang atau
dapat berdifusi dan hilang.pada beberapakasus, vesikel yang kosong
akan di transportasi kembali kebadan sel. Meskipun belumada penelitian
yang benar
 ACTION OF NEUROTRANSMITTERS
general characteristics
Neurotransmitter travels pre  post synaptic
Receptors associated with Ion channels and
enzyme(second messenger)
Acts in milliseconds
Activate both pre and post synaptic receptors.
More transmitter interact both pre and post
synaptically (Sp Rec & sp effects)
Chemical Synaptic Transmission

• 4 steps:
– Synthesis of transmitter
– Storage & release of transmitter
– Interaction of transmitter with
receptor in postsynaptic membrane
– Removal of transmitter from synaptic
cleft
CLASSIFICATION: BIOCHEMICALLY
 PYSIOLOGICALLY

EXCITATORY INHIBITORY
Eg:Acetylcholine GABA
Aspartate Glycine
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotonin
Excitatory neurotransmitters:
Inhibitory neurotransmitters:
 Classifying Neurotransmitters
• Once divided into 2 classes:
– Cholinergic – use acetylcholine (ACh)
– Adrenergic - use norepinephrine or
epinephrine
• Now know there are many more types
• 2 large classes:
– Small molecules
– Neuroactive peptides (short chains of
amino acids)
 Manufacture of Large Molecule
Transmitters
• Peptides
– Examples: substance P, somatostatin, leu-enkephalin,
met-enkephalin, vasoactive intestinal polypeptide (VIP),
bombesin
• Occurs in soma
• Peptide synthesized in rough endoplasmic reticulum
• Packaged in Golgi apparatus
• Transported down axon to presynaptic ending of the axon
terminal
– secretory vesicles transported down axon by
orthograde axonal transport
 Manufacture of Small Molecule
Transmitters
• Small molecule transmitters (amino acids and amines)
– Examples of amino acid neurotransmitters: gamma-amino
butyric acid (GABA), glutamate (Glu), glycine (Gly)
– Examples of amine neurotransmitters: acetylcholine (ACh),
dopamine (DA), epinephrine, histamine, norepinephrine (NE),
serotonin (5-HT)
• Occurs in axon terminal
• Precursor molecule is transformed by synthetic enzyme into
neurotransmitter molecule
• Neurotransmitter molecules are gathered by transporter
molecules and packaged in synaptic vesicles
Small Molecule Neurotransmitters
• Nine such substances are accepted as
neurotransmitters:
– 8 are amines
– The non amine is ATP
• Synthesis of these neurotransmitters is
catalyzed by enzymes
• Acetylcholine - perhaps the most
important small molecule transmitter
Acetycholine:
SYNTHESIS:

• Vasodilation,
• cardiac inhibition,
• GI peristalsis;
• control of thought, mood, sleep, muscles, bladder,
sweat glands
 Acetylcholine
• Acetylcholine is the transmitter used by
motor neurons of the spinal cord
• Released at all vertebrate neuro-
muscular junctions
• Present in autonomic & parasympathetic
neurons
• Used in many brain synapses
 Acetylcholine Synthesis
• Synthesis uses the enzyme choline
acetyltransferase (ChAT)
• Takes acetyl group from acetyl CoA in
cytosol
• Takes choline from extracellular fluid
(rate limiting step)
 Cholinergic Neurons
• Use acetylcholine as a neurotransmitter
• 2 types of receptors
– Nicotinic receptor - transmitter-gated ion
channel
– Muscarinic receptor - G-protein-coupled
receptor using short-cut pathway to close
potassium channel
• Removal
– degraded by acetylcholine esterase (AChE)
– AChE is the target of many nerve gases and
insecticides
 Biogenic Amine Transmitters
• The rest of the 8 amines
• Includes serotonin & the
catecholamines (dopamine, epinephrine
& norepinephrine)
• All catecholamines are synthesized from
the amino acid, tyrosine.
– share a common biosynthetic pathway
– pathway uses 5 enzymes
M
O
• Diproduksi sistem saraf di otak
N
O • Macamnya al:
A • 1. Catecholamine:
M a. Epineprin: dihasilkan adrenal
medulla
I
b. Norepineprin: terdapat di
N
sistem saraf & adrenal cortex
E
 c. Dopamin: potensial
posinaptik jadi eksitatori/
inhibisi (tergantung reseptor)

– Inhibitori: penyebab
skizofrenia, Parkinson 
tremor, kejang, keseimbangan
badan tergg
– L-DOPA (stimulan dopamin) 
gejala Parkinson berkurang
 parkinson

skizofren
T
E
R Fisiologi dopamin
M
I
N
A
L

B
U
T
T
O
N
– Kelebihan dopamin 
simtom skizofrenia:
halusinasi, delusi, kacau
pikiran. Atasi dengan obat
pengeblok neurodopamin
– Kokain: sebabkan reabsorbsi
dopamin berkurang, dopamin
banjir  kelumpuhan
otot (reseptor Ach terblok
dopamin, shg tak bisa kontrol
gerakan otot)
– Perpaduan
norepineprin &
dopamin =
katekolamin
• Kekurangan 
depresi
• Kelebihan 
penderita adiksi obat
– Bersifat eksitatoris
– Berperan dalam proses
adiksi
Epinefrin
Meningkatkan detak jantung dan melakukan dilatasi jalan napas
untuk meningkatkan fungsi nafas dan menyempitkan pembuluh darah di dalam
usus dan kulit.Bekerja bersama dengan norepinephrine yang dilepaskan oleh
kelenjar adrenal.
• 2. Indolamin, terdiri
a. Serotonin (5-hydroxytryptamin /5-
HT): hambat potensial posinaptis
– Atur gugahan/mood, kontrol makan, tidur-
bangun, emosi, regulasi rasa sakit, ingatan,
belajar, pengaturan suhu tubuh, perilaku
seksual
– Sebabkan tidak mimpi saat terjaga
– LSD: mengeblok neuro serotonin  serotonin
minim, shg bermimpi saat terjaga/halusinasi
 Dopaminergic Neurons
• Use dopamine, norepinephrine, or
epinephrine as neurotransmitters
• Synthesis pathway:
– Tyrosine hydroxylase (TH) makes tyrosine
into dopa
– Dopa decarboxylase makes dopa into
dopamine (DA)
• If the neuron is dopaminergic, the
pathway stops here
Noradrenergic & Adrenergic Neurons
• The synthesis pathway continues from
dopamine:
– Dopamine beta-hydroxylase (DBH) makes
dopamine into norepinephrine
• If the neuron is noradrenergic, the pathway
stops here,
• Or the pathway can continue:
– Phentolamine N-methyltransferase (PNMT)
makes norepinephrine into epinephrine
• If the neuron is adrenergic, the pathway goes
the whole way to this point
Summary of Catecholamine Synthesis
• All catecholamines have a catechol nucleus & a 3,4-
dihydroylated benzene ring
• The 1st enzyme, tyrosine hydroxylase, converts
tyrosine to L-dihydroxyphenylalanine (L-DOPA)
• L-DOPA is a precursor for all catecholamines
• The 2nd step converts L-DOPA to dopamine & CO2
• The 3rd step converts dopamine to norepinephrine
• The 4th step converts norepinephrine to epinephrine
 SYNTESIS

Catecholamines:

Dopamine:
Control of movements(parkinsonism)
Induction of vomiting
Inhibition of prolactin secretion
Stimulation of GnRH
Schizophrenia
Catecholamine Synthesis
 Norepinephrine
• In the CNS, norepinephrine is used by
neurons of the locus coeruleus, a
nucleus of the brainstem with complex
modulatory functions
• In the peripheral nervous system,
norepinephrine is the transmitter of the
sympathetic nervous system
• Norepinephrine can then be converted
to epinephrine
 Removal of Catecholamines

• All three catecholamines are removed

by selective reuptake by the presynaptic
axon terminals
• They are either reused or degraded by
monoamine oxidase (MAO)
• Amphetamines and cocaine block the
reuptake of catecholamines, thereby
prolonging their synaptic action
Norepinephrine
Dopamine & Norepinephrine
Close Cousins?
Neropinefrin
Memiliki konsentrasi tinggi di dalam locus ceruleus serta dalam
konsentrasi sekunder dalam hippocampus, amygdala, dan kortex cerebral.
Dipindahkan dari celahsynaptic dan kembali ke penyimpanan melalui proses
reuptake aktif. Menghambat penembakan neuron dalam system saraf pusat,
tetapi membangkitkan otot jantung, jantung, usus dan alat urogenitalia. Ia
juga membantu mengendalikan kewaspadaan serta berfungsi dalam proses
pembelajaran dan memory
 Serotonin
• Derived from the amino acid, tryptophan
• Belongs to a group of compounds called
indoles
• Serotonergic neurons are found in the
brainstem
• Involved in regulating attention & other
complex functions
 Serotonin Synthesis
• 2 enzymes synthesize serotonin
• Synthesis:
• Tryptophan (from the diet via the blood
stream) is converted to 5-HTP by
tryptophan hydroxylase
• 5-HTP is converted to serotonin (5-HT)
by 5-HTP decarboxylase
 Serotonergic Neurons
• Use serotonin (5-HT) as a neurotransmitter
• Because tryptophan comes from the diet,
serotonergic neurons can be quickly affected
by dietary deficiencies in tryptophan
• Removal:
– Selective reuptake by the presynaptic axon
terminals
– Either reused or degraded by MAO
Serotonin
Importance of Amine Transmitters
• These compounds (serotonin, dopamine, epinephrine
& norepinephrine) play an important role in mental &
neurological dysfunction:
• Depression
– antidepressant drugs enhance neurotransmission
at serotonergic and adrenergic synapses
• Schizophrenia
– involves dopaminergic neurotransmission
• Drug addiction
• Parkinson's disease
– associated with decreased production of dopamine
– treated with L-DOPA
 Neuropharmacology
• Many neurological diseases and mental
disorders represent malfunctions of the
synaptic transmission
• These can often be treated by drugs which
restore synaptic transmission.
• Inhibitors or receptor antagonists:
– bind to postsynaptic receptor and block normal
action of a neurotransmitter
• Receptor agonists:
– mimic the actions of normal neurotransmitters
What Drugs?
 Histamine
• Acts as a local
hormone (autocoid)
• Involved in control
of blood vessels,
inflammatory
response, etc.
• Also acts as a
neurotransmitter in
invertebrates
 Histamine:
SYNTHESIS:
 Amino Acid Transmitters
• Unlike acetylcholine & biogenic amines, these are
universal parts of cells
• Glycine & glutamate are common parts of
proteins
• GABA
– is synthesized from glutamate
– is a major inhibitory transmitter at many sites in brain
• Common amino acids act as transmitters in some
neurons, not in others
– shows that the presence of a substance doesn’t make
it a transmitter
 Amino acid:
SYNTHESIS:
A
S  1. Asam glutamik, ditemukan di seluruh
A otak, eksitatori
 2. GABA, banyak di otak & spinal cord,
M inhibitori
A  Abnormalitas  epilepsi
 Reseptor GABA-A (Gamma Amino
M Butyrid Acid)-A pengikat 3 transmiter:
 Steroid
I  Transquilizing (benzodiazepam) 
meredakan kecemasan, tidur, turunkan
N agresi, otot rileks
 Barbiturat/alkohol
O
• 3. Glicyne, terdapat di otak
& spinal cord, inhibitori
–Tetanus: zat kimia
pengeblok aktvts sinapsis
glisin, hilangkan hambatan
sinapsis  otot kontraksi
terus²an (kejang²)

–Racun laba-laba hitam

(black widow) bersifat
eksitatori thd sel produsen
Ach  gerakan otot
meningkat, tremor, kejang
GABA (Asam gama-aminobutirat)
Ditemukan pada seluruh system saraf pusat. GABA berlokasi di
Hipotalamus,hipocampus, korteks, serebelum,basal ganglia, medula spinalis,
retina. GABA pentingdidalam otak karena menjaga penembakan banyak
neuron. Ia membantu ketepatansinyal yang dibawa dari satu neuron ke
neuron berikutnnya
Glutamat
• merupakan neurotransmitter excitatory utama pada otak dimana hampirtiap
area otak berisi glutamate.
• Glutamat memiliki konsentrasi tinggi di corticostriataldan di dalam sel
cerebellar. Gangguan pada neurotrasmitter ini akan berakibat gangguanatau
penyakit bipolar afektif dan epilepsi.
Oksitosin
Merupakan sebuah hormon dan neurotransmitter yang memainkan
peranan pentingdalam pengalaman cinta dan ikatan anatar manusia.
Epinefrin
Meningkatkan detak jantung dan melakukan dilatasi jalan napas
untuk meningkatkan fungsi nafas dan menyempitkan pembuluh darah di dalam
usus dan kulit.Bekerja bersama dengan norepinephrine yang dilepaskan oleh
kelenjar adrenal.
 ATP & Adenosine
• ATP & degradation products such
adenosine can serve as neurotransmitters
at some synapses
 Neuroactive Peptides
• More than 50 pharmacologically active peptides
are known
• Serve important functions:
– Some modulate emotions
– Some located in regions of brain involved in
pain and pleasure perception
– Substance P
– Endorphins/Enkephalins
• Others respond to stress
– Endorphins
Families of Neuroactive Peptides
• Grouped into families:
– Opioid
– Neurohypophyseal
– Tachykinins
– Secretins
– Insulins
– Somatostatins
– Gastrins
 Transmitter Binding
• The same transmitter can bind different
receptors, resulting in different actions.
• Receptor binding determines the effect, not
the transmitter itself.
• In related animals, each type of transmitter
binds to a family of receptors and is
associated with certain functions
• Example: acetylcholine = synaptic excitation
at neuromuscular junctions in vertebrates
Transmitter Binding
 Dale's Principle
• Dale postulated that each neuron releases
one and only one neurotransmitter
• This is generally true for amino acid and
amine neurotransmitters
– however, a peptide often accompanies the
amino acid or amine
• Sometimes many peptides are released
from one neuron
 Which Neurotransmitter?
• How is the neurotransmitter traffic
controlled?
– Slow or intermittent activity causes the
release of the amino acid or amine transmitter
– Only sustained high levels of activity, or many
long bursts cause the peptides to be released
 OVERVIEW
.