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KANAL ION SEBAGAI TARGET AKSI OBAT

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Reseptor melibatkan fungsi kanal ion sebagai target

aksi obat

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Berdasarkan aktivasinya, kanal ion di bagi:

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VGIC (voltage-gated ion channels), kanal ion

teraktivasi voltase
LGIC (ligand-gated ion channels), kanal ion
teraktivasi ligan
Acetylcholine (Ach)
GABA
Glisin
Glutamate
Kanal ion teraktivasi kekuatan mekanik/strech

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Struktur Kanal ion

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Struktur kanal ion

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Drug Targets

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Nifedipin

Fitur penting:
1. Gating (opening dan closing)
Fitur apa yang membuat kanal membuka
dan menutup?
2. Ion selectivity
Mengapa kanal K+ tidak bisa dilewati Na+?
3. Fitur molekuler terkait fungsi

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Struktur apa yang menentukan fungsi dari

kanal ?

Gating:
Ligands

Controll
ed by
different
types of
stimuli:

Phosphorylation

Voltage

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Stretch

Gating

Involves conformational changes in the ion

channel protein.
Each channel protein has two or more
conformational states (e.g., open & closed) that
are relatively stable.

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Each stable conformation represents a different

functional state.

3 modes of gating:

Ion Selectivity:
0.095 nm

Why does a K+ channel not allow Na+

through?

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0.133 nm

A class of ion channels gated (opened and closed) by the trans-membrane potential
difference (voltage).
There are many, many, types. Among these are:
- Na+ Channels
- K+ Channels
- Ca2+ Channels

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- Cl- Channels.

There are actually many types of Na, K, Cl, and

Ca Channels, classified according to
pharmacology, physiology, and more recentlymolecular structure.

Terlibat dalam:
1. Inisiasi dan propagasi POTENSIAL AKSI
2. Kontrol traansmisi sinaptik
3. Homeostasis ion intraselular

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4. Aspek lain fungsi intraselular

Beraksi sebagai aktivator enzim intraseluler

Koordinasi sinyal antara membran sel dan organel

internal (e.g., mitochondria).

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Potensial sel
Depolarisasi
Repolarisasi
Hiperpolarisasi

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Resting potensial

Voltage-Gated Ion Channels

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CLOSED

Repolarisasi

OPEN

Depolarisasi

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Na+ Channel

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Cartoon representation of the typical voltage-activated

sodium channel

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The theory is
that the inactivation gate
swings shut, turning off
the channel

Sodium Channels - Function

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Play a central role in the transmission of

action potentials along a nerve
Can be in different functional states (3)
-A resting state when it can respond to a
depolarizing voltage changes
-Activated, when it allows flow of Na+ ions
through the channel
-Inactivated, when subjected to a
suprathreshold potential, the channel will not
open

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Na+ channel open state inactivation

Na+

Na+

Closed

Open
Na+

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Inactivated

Na + Channel
Blockers/Pharmacological Agents

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Fenitoin, karbamezepin, lamotigrin antiepilepsi

Lidokain, prokain anestesi lokal
Amiodaron, disopiramida, prokainamid
anti-aritmia
Tetrodotoxin (TTX) (racun)
Mexilitine
Ketamine

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Kanal ion Calcium

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Calcium as Second Messenger

Neuronal excitibility and secretion:

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Increase of [Ca++] induces fusion of the synaptic vesicles with the plasma mambrane =>
this causes exocytosis of neuro-transmitters into the synaptic cleft.

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Bagaimana Ca2+ berperan dalam kontraksi otot

polos?

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Microstructure of Skeletal
Muscle (myofibril)

41

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Thick filament: Myosin (head and tail)

Thin filament: Actin, Tropomyosin, Troponin
(calcium binding site)

42

Calcium as Second Messenger

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Calmodulin:
ubiquitous expression; binds 4 Ca++-ions; acts through stimulation of
CALMODULIN KINASES (CaMK), contohnya MLCK
or protein phosphatases (Calcineurin); also activates cAMP
phosphodiesterase

Troponin C:
restricted expression, regulates contraction of skeletal and heart muscle

MLCK

Myosin

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The calcium-binding regulatory protein calmodulin undergoes

a conformational shift on binding to calcium, which enables it
to bind and activate other proteins. [Part (a) PDB ID 3CLN.]

Bagaimana Ca2+ berperan dalam kontraksi otot

jantung?

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Contraction (=actin-myosin
interaction) controlled by
proteins on actin filaments
(tropomyosin w/ troponin)
Troponin I inhibits formation
of cross-bridges between
actin and myosin => muscle
relaxed.
Troponin C combines with
Ca2+-ions and blocks the
action of Troponin I =>
muscle contracted

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Contoh obat yang beraksi pada kanal ion Ca2+

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CCB (Calcium Channel Blocker) : Nifedipin, verapamil, diltiazem

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Perkembangan CCB

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Nifedipin (Norvasck, Pfizer)

Amlodipin
Azelnidipin, Isradipin
Cilnidipin

K Channels

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http://diabetesmanager.pbworks.com/w/page/17680187/Exercise%20and%20the%20Regulation%
20of%20Blood%20Glucose

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http://iopscience.iop.org/2043-6262/3/1/013001/article

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Jenis kanal Cl

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Kanal Cl teraktivasi voltase

Kanal Cl teraktivasi cAMP
Kanal Cl teraktivasi mekanik
Kanal Cl teraktivasi calcium
Kanal Cl teraktivasi ligan

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Kanal ion Cl teraktivasi voltase

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Struktur dan mekanisme regulasi

pada kanal Cl

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Lubiprostone

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THANK YOU