VOLTAGE – GATED

ION CHANNEL
Kanal Ion Teraktivasi Voltase

Kelompok 1
What is Voltage Gated Ion Channel ?
Ion channels are proteins that contain a pore for the passage of ions across membranes. Opening and
closing of the pore " gating" can be controlled by a number of different factors.

This includes :
1. Binding of ligands such as neurotransmitters (ligand-gated ion channels; LGIC)
2. Chemical modifications such as phosphorylation whilst a number of ion channel types are sensitive to
changes in the membrane potential. (voltage-gated receptors) ;basically they detect changes in the local
electrochemical gradient across membranes which is measured in volts.
Classification Of Voltage-
Gated Ion Channel
Ca2+
Na+
K+
 Activation
Mechanism
Ion channels respond to changes in transmembrane
potential. Channels open in response to depolarization
and close when hyperpolarization occurs.
For example:
Ion Na+ and K+ = Nerve and muscle cells
Ion Ca2+ = Controls the release of neurotransmitters at presynaptic nerve endings
01 Na Channel
Na channels play an important role in the initiation
and progression of neuronal action potentials.
Neuronal depolarization of several millivolts can
be caused by activation of glutamate receptors,
especially AMP receptors, which then activate
sodium channels so that channels open and sodium
enters the cell.

This channel only opens for a few milliseconds,

triggering depolarization and thus an action
potential. After that the channel becomes inactive,
but 1% of the sodium current is still going through
the channel causing persistent sodium current
(INAP), INAP will lower the action potential
threshold causing burst firing which then becomes
repeated.
02 Ca2+ Channel
Calcium channels there are many
different cell types that are active in
membrane depolarization and mediate
calcium influx in response to action
potentials and depolarizing signals.

Calcium entering cells through voltage-

gated calcium channels serves as a second
messenger of electrical signaling that
initiates many different cellular events.
03 K+ Channel
The voltage-gated potassium channel is activated
by depolarization, and the outflow of potassium
ions through the repolarization of the membrane
potential to terminate the action potential,
hyperpolarizes the membrane potential
immediately after the action potential, and plays
a key role in the regulation of the resting
membrane potential. In this way, potassium
channels control electrical signals and regulate
transient calcium and ion fluxes in nonexcitable
cells.
The first voltage-gated potassium channel was
cloned from Drosophila based on the mutation
causing the Shaker phenotype. They consist of
four transmembrane subunits, each of which is
analogous to a single domain of the main
subunit of a sodium or calcium channel.
Pharmacodynamics of Phenytoin

The voltage-gated sodium channels are coded for by the SCN (SCN1 A, SCN2A,
and SCN3A) family or genes, which has members expressed in heart and skeletal
muscle as well as the peripheral and central nervoud systems. Mutations in
SCN1A are associated with epilepsy; over 500 variants have been reported,
including those associated with Dravet syndrome also known as severe
myoclonic epilepsy of infancy (SMEI). Epilepsy-associated variants have also
been reported in SCN2A but few variants in SCN3A have been documented.
Phenytoin targets voltage-gated sodium channels in the brain and binds the
SCN2A
Pharmacodynamics of Carbamazepin
Carbamazepine is chemically a tricyclic antidepressant. Carbamazepine is used as
the first choice in the treatment of partial and tonic-clonic seizures.

Carbamazepine mechanism of action is to block Na . channels+, which results in an

influx of Na . ions+ into the cell membrane is reduced and inhibits the generation of
action potentials by continuous depolarization of the neuron.

Side effects that often occur with the use of carbamazepine are visual disturbances
(double vision), dizziness, weakness, drowsiness, nausea, unsteadiness (unable to
stand upright) and Hyponatremia. The risk of these side effects increases with age
Barbiturat (Fenobarbital)
Fenobarbital merupakan obat yang efektif untuk kejang parsial dan kejang tonik-klonik .
Efikasi, toksisitas yang rendah, serta harga yang murah menjadikan fenobarbital obat
yang penting untuk tipe-tipe epilepsi ini.
Mekanisme kerja fenobarbital terletak pada kemampuannya untuk menurunkan konduktan
Na dan K. Fenobarbital menurunkan influks kalsium dan mempunyai efek langsung
terhadap reseptor GABA (aktivasi reseptor barbiturat akan meningkatkan durasi
pembukaan reseptor GABAA dan meningkatkan konduktan post-sinap klorida). Selain
itu, fenobarbital juga menekan glutamate excitability dan meningkatkan postsynaptic
GABAergic inhibition.
Dosis awal penggunaan fenobarbital 1-3 mg/kg/hari dan dosis pemeliharaan 10-20 mg/kg 1
kali sehari.
Efek samping SSP merupakan hal yang umum terjadi pada penggunaan fenobarbital. Efek
samping lain yang mungkin terjadi adalah kelelahan, mengantuk, sedasi, dan depresi.
Penggunaan fenobarbital pada anak-anak dapat menyebabkan hiperaktivitas.
Fenobarbital juga dapat menyebabkan kemerahan kulit, dan Stevens-Johnson syndrome
Asam valproat
Asam valproat merupakan pilihan pertama untuk terapi kejang parsial, kejang absens, kejang mioklonik, dan
kejang tonik-klonik.

Mekanisme kerja asam valproat dapat meningkatkan GABA dengan menghambat degradasi nya atau mengaktivasi
sintesis GABA. Asam valproat juga  berpotensi terhadap respon GABA post sinaptik yang langsung menstabilkan
membran serta mempengaruhi kanal kalium.

Efek samping yang sering terjadi adalah gangguan pencernaan (>20%), termasuk mual, muntah, anorexia,
peningkatan berat badan, pusing, gangguan keseimbangan tubuh, tremor, dan kebotakan.
Hyperammonemia (gangguan metabolisme yang ditandai dengan peningkatan kadar amonia dalam darah)
umumnya terjadi 50%, tetapi tidak sampai menyebabkan kerusakan hati.

Interaksi. Penggunaan fenitoin dan valproat secara bersamaan dapat meningkatkan kadar fenobarbital dan dapat
memperparah efek sedasi yang dihasilkan. Valproat sendiri juga dapat menghambat metabolisme lamotrigin,
fenitoin, dan karbamazepin.  Obat yang dapat menginduksi enzim dapat meningkatkan metabolisme valproat. 
Hampir 1/3 pasien mengalami efek samping obat walaupun hanya kurang dari 5% saja yang menghentikan
penggunaan obat terkait efek samping tersebut 
Pharmacodynamics of Ethosuximide
Ethosuximide is used in the treatment of absence seizures.

Calcium channels are targets of several antiepileptic drugs. Ethosuximide inhibits

Ca2+ channels . The thalamus plays a role in the formation of rhythmic jerks
mediated by Ca2+ channels in absence seizures, so that Inhibition of these channels
will reduce jerks in absence seizures

The side effects of using ethosuximide are nausea and vomiting, body imbalance,
drowsiness, indigestion, unsteadiness (unable to stand up straight), dizziness and
hiccups
1. Ethosuximide treatment decreases calpain-mediated apoptosis-related gene
expression. We then determined whether the blocking of T-type Ca2+ channels can
downregulate cochlear cell gene expression. The family of T-type Ca2+ channels is
comprised of 3 main pore-forming α subunits: α1G, α1H and α1I (21). The mean
mRNA expression levels of the α1G, α1H and α1I subunits were decreased in the
cochleae of the ethosuximide-treated 8-week-old NOD/LtJ mice; a significant
difference was observed between the ethosuximide-treated group and the untreated
group for the α1H and α1I genes (P<0.01) (Fig. 5A).
2. There are 2 major intracellular apoptotic pathways. Extracellular stimuli can initiate an
extrinsic pathway (caspase-8) that activates the caspase family. Alternatively, the
intrinsic pathway involves intracellular calpain, which ultimately triggers apoptosis by
activating caspase-3 (Fig. 6) (22,23). Calpains (m-calpain and μ-calpain) are activated
by Ca2+(24). Our results suggested that ethosuximide treatment downregulated the
intrinsic apoptotic pathway (Fig. 5B and C).
 Pertanyaan dan Jawaban
1. Sebutkan obat-obat yang bekerja pada kanal kalium.
Jawab :
Beberapa jenis kanal ion K yang menjadi target molekuler obat dan contoh obatnya adalah sebagai berikut:
- Kanal Kv 1.3
Beberapa senyawa non peptida seperti dihidroquinolon, piperidin, dan alkoksipsoralen terbukti dapat memblok
kanal Kv
1.3.
- Kanal K Jantung
Kanal ini menjadi target aksi bagi obat-obat anti aritmia kelas III seperti amiodaron, bretilium, betanidin,
klofilium,
sotalol, ibutilid, dofetilid, dll.
- Kanal K Sensitive ATP
Obat golongan sulfonilurea seperti glibenklamid, tolbutamid, gplipzid, dan gliklazid merupakan penyekat selektif
terhadap kanal ion K+ yang sensitif terhadap ATP pada sel beta pankreatik.
References

Caterall W, 2013, Ion Channel Protein Superfamily, Elsevier, USA.

Dickenson J, Freeman F, Llyoyd C, dan Thode C, 2013, Molecular Pharmacology From DNA to Drug
Discovery, Wiley-Blackwill, USA.

Husna M, Kurniawan NS, 2017, Biomolecular Mechanism of Anti Epileptic Drugs, Universitas Brawijaya,
Malang.
William AC, 2011, Voltage-Gated Calcium Channels., Departement of Pharmacology University of
Washington. USA.
 Thank you
1. Faten Sarhan (N012211051)
2. Muh. Fadhil As’ad (N012211001)
3. Dede Haryono (N012211002)
4. Fathoanah Qiran (N012211003)
5. Grace Oktavia Soma Kasi’ (N012211006)
6. Khadijah Nurul Rahmah (N012211008)
7. Musdalifa (N012211009)
8. Djulfikri Mewar (N012211010)
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9. Nur Cahyani (N012211011)
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10. Nurfawardani (N01221012)
11. Haldi Nugraha HS (N0122110014)