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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:

• 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

Nifedipin

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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

• Struktur apa yang menentukan fungsi dari

kanal ?

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Gating:

Controll

ed by

different

types of

stimuli:

Stretch

Ligands

Voltage

Phosphorylation

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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.

• Each stable conformation represents a different

functional state.

3 modes of gating:

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Ion Selectivity:

• Why does a K+ channel not allow Na+

through?

0.133 nm

0.095 nm

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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

-Cl- Channels.

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

Ca Channels, classified according to

pharmacology, physiology, and more recently-

molecular structure.

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Terlibat dalam:

1. Inisiasi dan propagasi POTENSIAL AKSI

2. Kontrol traansmisi sinaptik

3. Homeostasis ion intraselular

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

• Resting potensial

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Voltage-Gated Ion Channels

CLOSED OPEN

Repolarisasi 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

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Sodium Channels - Function

• 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+ Na+

Na+

X

Closed Open

Inactivated

Na+ channel open state inactivation

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Na + Channel

Blockers/Pharmacological Agents

• Fenitoin, karbamezepin, lamotigrin anti-

epilepsi

• 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:

– 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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41

Microstructure of Skeletal

Muscle (myofibril)

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42

Thick filament: Myosin (head and tail)

Thin filament: Actin, Tropomyosin, Troponin

(calcium binding site)

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Calcium as Second Messenger

– 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

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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.]

MLCK

Myosin

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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

Bagaimana Ca2+ berperan dalam kontraksi otot

jantung?

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Contoh obat yang beraksi pada kanal ion Ca2+

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

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Perkembangan CCB

• Nifedipin (Norvasck, Pfizer)

• Amlodipin

• Azelnidipin, Isradipin

• Cilnidipin

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K+ Channels

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http://diabetesmanager.pbworks.com/w/page/17680187/Exercise%20and%20the%20Regulation%2

0of%20Blood%20Glucose

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

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Jenis kanal Cl

• 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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Str

uktu

r da

n m

ekan

ism

e r

egu

lasi

pa

da

ka

na

l C

l

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Lubiprostone

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