Reseptor Kanal Ion Sebagai

Target Aksi Obat

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)
Reseptor Ionotropik
• Transmisi signal melalui chanel ion
• Mengubah sinyal kimia menjadi sinyal elektrik
• Bertanggung jawab terhadap sinyal sinap
secara cepat
• Ikatan reseptor mengakibatkan perubahan
konformasi
• Memicu membuka/ menutup chanel ion
• Memfasilitasi ion spesifik
• Dijumpai pada sistem syaraf dan sel otot
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
• The major neurotransmitters are indicated on
the next slide.
 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 Effect on Neurotransmitter Drug that acts this way
release or availability
increase the number of impulses increased neurotransmitter nicotine, alcohol, opiates
release
release neurotransmitter from increased neurotransmitter amphetamines
vesicles with or without impulses release methamphetamines
release more neurotransmitter in increased neurotransmitter nicotine
response to an impulse release
block reuptake more neurotransmitter present in cocaine
synaptic cleft amphetamine
produce less neurotransmitter less neurotransmitter in synaptic probably does not work this way
cleft
prevent vesicles from releasing less neurotransmitter released No drug example
neurotransmitter
block receptor with another no change in the amount of LSD
molecule 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 oto.
 Aksi obat target asetilkolin
• Meningkatkan kadar asetilkolin pada sinaps:
– Blokir re uptake asetilkolin: hemikolinium
– Inhibitor kolinesterase: neostigmin, fisostigmin, galantamin
dll
• 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 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
transpors
• Meningkatkan pelepasan GABA:
Gabapentin
• Menghambat transporter GABA: tiagabin
• Menghambat GABA transaminase:
Vigabratin
Reseptor Glutamat
 Reseptor Glutamat
• Merupakan neurotransmitter pemicu
• Jenis reseptor ionotropik:
– Reseptor ionotropik: N-Metil D-Aspartat
(NMDA)
– Reseptor AMPA (a-Amino-3-hidroksi-5-metil-
4-isoksazil asam propionat (AMPA) dan
– reseptor Kainat
 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 gluatamat
menyebabkan aliran Na+ dan Ca2+ dan memicu proses di
sel post sinaps
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 penghanraean impuls ke pusat muntah
• Antagonis 5HT3 (ondansetron, tropisetron, zakoprid, granisteron)
mengatasi mual dan muntah akibat pemberian kemoterapi
 Jalur Serotonin
• Serotonin diakumulasi didalam vesikel penyimpanan
prasinaptik dengan bantuan vesicular monoamin
transporter, selanjutnya apa bila ada pacuan 5HT3 akan
terlepas ke celah sinaotik dan mengalami:
– Difusi menjauh dari sinap
– Metabolisme oleh MAO
– Aktivasi reseptor presinaptik
– Aktivasi reseptor sinaptik
– Reuptake oleh serotonin transporter
 Inhibitor SERT Selektif (SSRI)
• Sebagai antidepresan
• Memperlama aksi serotonin
• Contoh: fluoksetin, paroksetin,
klomipramin