Reseptor Kanal Ion Sebagai

Target Aksi Obat

• Overview of cell signaling
EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception 2 Transduction 3 Response

Receptor
Activation
of cellular
response
Relay molecules in a signal transduction pathway

Signal
molecule

Figure 11.5
• Reception: A signal molecule binds to a receptor
protein, causing it to change shape
• The binding between signal molecule (ligand)
– And receptor is highly specific
• A conformational change in a receptor
– Is often the initial transduction of the signal
• There are three main types of membrane
receptors
– Ion channel
– G-protein-linked
– Tyrosine kinases
• Ion channel receptors Signal
Gate
closed Ions
molecule
(ligand)

Ligand-gated Plasma
ion channel receptor Membrane

Gate open

Cellular
response

Gate close

Figure 11.7
• G-protein-linked receptors
Signal-binding site

Segment that
interacts with
G proteins

G-protein-linked Activated Inctivate

Plasma Membrane Signal molecule
Receptor Receptor enzyme

GDP
G-protein GDP GTP
CYTOPLASM (inactive) Enzyme

Activated
enzyme

GTP
GDP
Pi

Cellular response
Figure 11.7
• Receptor tyrosine kinases
Signal Signal-binding sitea
molecule
Signal
Helix in the molecule
Membrane

Tyr Tyr
Tyr Tyr Tyr Tyr
Tyrosines Tyr Tyr
Tyr Tyr Tyr Tyr
Tyr Tyr
Tyr Tyr Tyr Tyr

Receptor tyrosine
CYTOPLASM kinase proteins Dimer
(inactive monomers)

Activated
relay proteins

Cellular
Tyr Tyr P Tyr Tyr P P Tyr Tyr P
Tyr P
response 1
Tyr Tyr P Tyr Tyr P P Tyr
Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular
6 ATP 6 ADP
response 2
Activated tyrosine- Fully activated receptor
kinase regions tyrosine-kinase Inactive
(unphosphorylated (phosphorylated relay proteins
dimer) dimer)
Figure 11.7
Pendahuluan
• Reseptor kanal ion (Ligand-gated ion
channel Receptor) disebut pula sebagai
reseptor ionotropik
• Reseptor tegandeng protein G disebut juga
reseptor metabotropik
• Reseptor asetilkolin ada dua; nikotinik
(ionotropik) dan muskarinik (metabotropik)
 Bagaimana Penjagaan Potensial
Membran?
+++++++++++++++++++++++++++++
--------------------------
--------------------------
+++++++++++++++++++++++++++++
Ion di luar sel di dominasi oleh
ion Na+,sedangkan di dalam
sel di dominasi oleh K+
Terdapat perbedaan muatan
60 – 80 mV
Kondisi muatan negatif intra sel
disebut sebagai kondisi resting
potensial
Perbedaan konsentrasi ion
menyebabkan Na cenderung
masuk ke dalam sel, K
cenderung keluar sel
Bagaimana gradien
konsentrasi di jaga?
 Lanjutan…
• Peristiwa keluar masuknya ion disebut
leaking
• Peristiwa tersebut tidak diharapkan,
sehingga ion perlu dikembalikan pada
keadaan semula melulai transport aktif
• Pompa transport tersebut adalah
Na+/K+ATPase
 Depolarisasi dan hiperpolarisasi
• Masuknya ion Na+ ke dalam sel,menyebabkan
bertambahnya muatan + di dalam sel sehingga perbedaan
polaritas berkurang (depolarisasi membran)
• Perbedaan polarisasi menentukan pada penghantaran sinyal
pada sel syaraf.
• Secara normal kanal ion K+ akan membuka dan
menyebabkan kembalinya polaritas, akan tetapi jika
membuka berlebihan membuat perbedaan polaritas semakin
meningkat (kompartemen intrasel bermuatan negatif)
mengakibatkan terjadinya hiperpolarisasi sehingga terjadi
hambatan transmisi potensi aksi, pada SSP menimbulkan
depresi.
 What does a synapse look like?

Electron Micrograph

Microscopy with
Microscopy with Fluorescent Proteins
Fluorescent Proteins

Murthy_HHMI_teachers_2005_sub.ppt
Figure 48.12 A chemical synapse
 Keterangan Gambar
1. Impulse from action potential opens ion
channels for Ca++
2. The increased Ca++ concentration in the axon
terminal initiates the release of the
neurotransmitter (NT)
3. NT is released from its vesicle and crosses the
“gap” or synaptic cleft and attaches to a protein
receptor on the dendrite
 Key to Diagram (cont.)
4. Interaction of NT and protein receptor
open post-synaptic membrane ion
channel for Na+
5. After transmission the NT is either
degraded by an enzyme or taken back into
the pre-synaptic membrane by a
transporter or reuptake pump
 Neurotransmitters
• There are dozens of different neurotransmitters
(NT) in the neurons of the body.
• NTs can be either excitatory or inhibitory
• Each neuron generally synthesizes and releases a
single type of neurotransmitter
 Neurotransmitter
• Strict definition has changed through the years.
• Satisfaction of the experimental criteria for identification
of synaptic transmitters can lead to the conclusion that a
substance contained in a neuron is secreted by that neuron
to transmit information to its postsynaptic target
• Transmitters may produce minimal effects on bioelectric
properties, yet activate or inactivate biochemical
mechanisms necessary for responses to other circuits,
• The action of the transmitter may vary with the context of
ongoing synaptic events – enhancing excitation or
inhibition, rather than operating to impose direct excitation
or inhibition.
Rule Of Neurotransmitter
 Major Neurotransmitters in the Body
Neurotransmitter Role in the Body
Acetylcholine A neurotransmitter used by the spinal cord neurons to control muscles and
by many neurons in the brain to regulate memory. In most instances,
acetylcholine is excitatory.
Dopamine The neurotransmitter that produces feelings of pleasure when released by
the brain reward system. Dopamine has multiple functions depending on
where in the brain it acts. It is usually inhibitory.
GABA The major inhibitory neurotransmitter in the brain.
(gamma-aminobutyric acid)
Glutamate The most common excitatory neurotransmitter in the brain.
Glycine A neurotransmitter used mainly by neurons in the spinal cord. It probably
always acts as an inhibitory neurotransmitter.
Norepinephrine Norepinephrine acts as a neurotransmitter and a hormone. In the
peripheral nervous system, it is part of the flight-or-flight response. In the
brain, it acts as a neurotransmitter regulating normal brain processes.
Norepinephrine is usually excitatory, but is inhibitory in a few brain areas.
Serotonin A neurotransmitter involved in many functions including mood, appetite,
and sensory perception. In the spinal cord, serotonin is inhibitory in pain
pathways.
NIH Publication No. 00-4871
 Drugs Interfere with
Neurotransmission
• Drugs can affect synapses at a variety of
sites and in a variety of ways, including:
1. Increasing number of impulses
2. Release NT from vesicles with or without
impulses
3. Block reuptake or block receptors
4. Produce more or less NT
5. Prevent vesicles from releasing NT
 Drugs That Influence Neurotransmitters
Change in Neurotransmission
increase the number of impulses
release neurotransmitter from
vesicles with or without impulses
release more neurotransmitter in
response to an impulse
block reuptake
produce less neurotransmitter
prevent vesicles from releasing
neurotransmitter
block receptor with another
molecule
Effect on Neurotransmitter Drug that acts this way
release or availability
increased neurotransmitter nicotine, alcohol, opiates
release
increased neurotransmitter amphetamines
release methamphetamines
increased neurotransmitter nicotine
release
more neurotransmitter present in cocaine
synaptic cleft amphetamine
less neurotransmitter in synaptic probably does not work this way
cleft
less neurotransmitter released No drug example
no change in the amount of LSD
neurotransmitter released, or caffeine
neurotransmitter cannot bind to
its receptor on postsynaptic
neuron
NIH Publication No. 00-4871
Reseptor Asetilkolin Nikotinik
Reseptor asetilkolin nikotinik
• Banyak terdapat pada neuromuscular junction
(sinaps antara syaraf motorik dan serabut otot)
• Hantaran potensi aksi pada ujung sinaps memacu
terbukanya kanal Ca2+, memacu pelepasan
asetilkolin. Interaksi dengan reseptor
menyebabkan terbukanya kanal ion Na+,
masuknya Na+ pada serabut otot menyababkan
depolarisasi membran dan membuka kanal Ca2+,
keluarnya Ca2+ dari retikulum sarkoplasmik
memacu kontraksi otot.
 Aksi obat target asetilkolin
• Meningkatkan kadar asetilkolin pada sinaps:
– Blokir re uptake asetilkolin: hemikolinium
– Inhibitor kolinesterase: neostigmin, fisostigmin, galantamin ,
donepezil, rivastigmin yang digunakan dalam pengobatan
alzheimer, glaukoma, myasthenia gravis.
• Mengurangi asetilkolon pada sinaps
– Menghalangi masuknya asetilkolin pada vesikel: vesamikol
• Interaksi dengan Asetiklolin reseptor
– Kompetisi dengan asetilkolin (non depolarizing agent): kurare
dan tubokurarin, memblok dan menyebabkan kelumpuhan otot
– Memperlama depolrasisi (depolarizing blocking agent):
suksinilkolin (hidrolisis lebih lama dari asetil kolin) dan
suksametonium, memperlama depolarisasi, menghambat
transmisi impuls berikutnya
 GABA and the GABA-a
Receptor
• GABA is a neurotransmitter that has an
inhibitory effect on neurons.
• When GABA attaches to its receptor on the
postsynaptic membrane, it allows Cl- ions
to pass into the neuron.
• This hyperpolarizes the postsynaptic
neuron to inhibit transmission of an
impulse.
 Tempat ikatan pada reseptor
GABAa
• Interaksi dengan golongan barbiturat
(barbiturat site)
• Interaksi dengan benzodiazepin
(benzodiazepin site)
• Interaksi dengan steroid (steroid site)
• Interaksi dengan pikrotoksin
 Obat-obat pada GABA
• Antagonis: gabazin, sekurinin, pitrazepin,
pikrotoksin (beikatan pada sisi lain , menyekat
kanal ion Cl-), menyebabkan konvulsi
• Golongan benzodiazepin meningkatkan afinitas
reseptor terhadap GABA, meningkatkan frekuensi
kanal ion (diazepam, klordiasepoksid, lorazepam)
• Barbiturat, etanol dan anastesi, menngikat reseptor
GABA dan memperlama pembukaan kanal ion Cl-
 Aksi pada Jalur sintesis dan
transport pada pengobatan epilepsi
• Meningkatkan pelepasan GABA:
Gabapentin
• Menghambat transporter GABA: tiagabin
• Menghambat GABA transaminase:
Vigabratin
Reseptor Glutamat
 Reseptor Glutamat
• Merupakan neurotransmitter pemicu
– Jenis reseptor metabotropik
– Jenis reseptor ionotropik:
– Reseptor ionotropik (permiabel thd ion Ca2+ dan
Na+):
• N-Metil D-Aspartat (NMDA)
• Reseptor AMPA (a-Amino-3-hidroksi-5-metil-4-
isoksazil asam propionat (AMPA) dan
• reseptor Kainat
Jalur Sintesis
(I) The Glutamate System
L-Glutamate: “the king of neurotransmission”

41
01.07.2010
 The Glutamate System:
(Moghaddam, 2005)

• Glutamate is the major excitatory neurotransmitter in

the central nervous system and the most prevalent one
(the king of neurotransmission)
• Nearly 70% of the neurons in the brain, including all
neurons that project from the cerebral cortex, are
believed to use glutamate as their neurotransmitter.
• In mammalians‘ brains, glutamate is balanced with
GABA (main inhibitory chemical transmitter): > E/I
balance (accelerator/break)
• Both transmitters influence almost every other
chemical transmitter and brain areas.

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01.07.2010
 Table 1. Classes of CNS Transmitters

Neurotransmitter % of Brain Function Primary

Synapses Concentration Receptor Class

Monoamines 2-5 nmol/mg Slow change in GPCRs

Catecholamines: DA, NE, protein excitability (secs)
EPI (low)
Indoleamines: serotonin
(5-HT)
Acetylcholine (ACh) 5-10 nmol/mg Slow change in GPCRs
protein excitability (secs)
(low)
Amino acids μmol/mg Rapid inhibition Ion channels
Inhibitory: GABA, glycine 15-20 protein (msecs)
(high)
Excitatory: Glutamate,
aspartate 75-80 μmol/mg Rapid excitation Ion channels
protein (msecs)
(high)

43
 Table 2. Major Neurotransmitter Receptors in the CNS

Neurotransmitter Receptor Subtypes G Protein-Coupled (G) vs.

Ligand-Gated Ion Channel (LG)
DA D1 G
D2 G
D3 G
G
D4
G
D5

NE/EPI α1 G
α2 G
β1 G
G
β2
G
β3

5-HT 5-HT1A G
5-HT1B G
5-HT1D G
G
5-HT2A
G
5-HT2B G
5-HT2C LG
5-HT3 G
5-HT4

ACh Muscarinic M1 G
Muscarinic M2 G
Muscarinic M3 G
G
Muscarinic M4
LG
Nicotinic

Glutamate NMDA LG
AMPA LG
Kainate LG
Metabotropic G
44
GABA A LG
B G
 Possible therapeutic applications

– Multifacet ischemia, – Diabetes,

– Epilepsy, – Multiple Sclerosis,
– Parkinson's disease, – Schizophrenia,
– Alzheimer’s disease, – Anxiety,
– Hyperalgesia, – Depression,

45
01.07.2010
 Glutamate Receptors:

• Glutamate acts via two classes of receptors

which spread in both neurones and glial cells:
– Ligand gated ion channels (Ionotropic receptors):
• Four groups (AMPA, NMDA, Kinate and
Delta receptors).
– G-protein coupled (Metabotropic receptors).
• They are further broken down into three groups
and eight subgroups: (mGlu1-mGlu8).

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01.07.2010
47
01.07.2010
 FUNCTIONAL CHARACTERISTICS OF
IONOTROPIC GLUTAMATE RECEPTORS

Receptor family Characteristics Agonists

AMPA High affinity for AMPA (~10 nM) AMPA>Glu>KA

High affinity for kainate

KA (10 nM- KA1,2; 75 nM- GluR5-7) KA>Glu>>AMPA

Hign affinity for glutamate; voltage-

NMDA dependent blockade by Mg2+; glycine is Glu>NMDA
a co-agonist

AMPA – -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

KA – kainic acid
NMDA – N-methyl-D-aspartate
• Reseptor NMDA glutamat memiliki afinitas dengan glutamat
lebih besar
• Terdapat pda cortex cerebral dan hippocampus yang berfungsi
dalam proses memori dan belajar
• Dapat diaktivasi pula oleh glutamat
• Reseptor NMDA pada medula spinalis berperan sebagai
penghantar nyeri, antagonis (ketamin) menghambat nyeri
• Digunakan pula dalam patofisiologi demensia AIDS,
Alzheimer, trauma otak dan stroke
• Stimulasi berlebih menyebabkan masuknya ion Ca2+
sehingga memacu proses biokimia berlebih yang
menyebabkan kematian sel.
• Memantin (antagonis NMDA) berfungsi untuk mencegah
degenerasi syaraf
Namenda (Memantine)
• Namenda is an N-methyl D-aspartate
(NMDA) antagonist that regulates the
activity of glutamate in the brain. Glutamate
plays a key role in memory and learning,
but excess glutamate can lead to the
disruption of nerve cell communication or
nerve cell death.
• Studies involving Namenda have shown that the
drug can slow the rate of decline in thinking and
the ability to perform daily activities in individuals
who have moderate to severe Alzheimer's disease
• A dysfunction of glutamatergic neurotransmission
is thought to be involved in the etiology of AD.
• Namenda is available in generic form (memantine
HCL).
 Mekanisme aktivasi Reseptor
Glutamat
• Aktivasi NMDA pada otak diawali aktivasi reseptor
glutamat non-NMDA, pada kondisi normal kanal ion
NMDA diblok oleh Mg2+, pelepasan glutamat dari
presinap akan berikatan dengan reseptor non-NMDA
membuka kanal ion Na+, masuknya Na+ menyebabkan
depolarisasi parsial membran selanjutnya memicu
pelepasan Mg2+ dan membuka kanal NMDA, kedua
reseptor terbuka sebagai respon terhadap glutamat
menyebabkan aliran Na+ dan Ca2+ dan memicu proses di
sel post sinaps
NMDA receptor
as a coincidence
detector :
requirement for
membrane
depolarization

54
NMDA receptor is Ca++ permeable

55
Reseptor Serotonin
 Reseptor Serotonin
• 5 hidroksitriptamine (5HT) memiliki 14 sub tipe
• 5 HT3 yang terikat pada kanal ion
• 5HT3 terdapat pada spinal cord, cortex dan hippocampus
• Reseptor ini terikat pada kanal ion yang tidak selektif, aktivasi menyebabkan
terbukanya kanal kation menyebabkan arus depolarisasi yang cepat dan
singkat akibat pergerakan ion K+ dan Na+.
• Terdapat pula pada chemoreceptor trigger zone (CTZ) yang berperan dalam
penghantaran impuls ke pusat muntah
• Kemoterapi/ radiasi enyebabkan kerusakan sel dan memicu pelepasan
serotonin dari entkromafin, dan berikatan dengan sel syarag pada saluran
cerna menuju pusat muntah.
• Antagonis 5HT3 (ondansetron, tropisetron, zakoprid, granisteron) mengatasi
mual dan muntah akibat pemberian kemoterapi
Serotonin dan Migrain
• Neurotransmiter terlibat dalam berbagai
penyakit:
– Depresi
– Fobia
– Skizofrenia
– Panik
– Migrain
– Gannguan cerna
 Jalur Serotonin
• Serotonin diakumulasi didalam vesikel penyimpanan
prasinaptik dengan bantuan vesicular monoamin
transporter, selanjutnya apa bila ada pacuan 5HT3 akan
terlepas ke celah sinapik dan mengalami:
– Difusi menjauh dari sinap
– Metabolisme oleh MAO
– Aktivasi reseptor presinaptik
– Aktivasi reseptor sinaptik
– Reuptake oleh serotonin transporter
• Reseptor 5-HT3 terdapat pada spinal cord,
cortex dan hippocampus
• Reseptor ini berikatan dengan kanal ion
tidak selektif
• Aktivasi menyebabkan kanal kation
membuka dan memicu arus depolarisasi
cepat dan singkat
• Reseptor ini terdapat pula pada
chemoreceptor triger zone
 Inhibitor SERT Selektif (SSRI)
• Sebagai antidepresan
• Depresi dimanifestasikan sebagai akibat
kekurangan serotonin
• Memperlama aksi serotonin
• Contoh: fluoksetin, paroksetin,
klomipramin