Voltage Gated Ion Channels

(VGICs) :
Target Untuk Obat
Antikonvulsant

Oleh :
Yuli Asnanik
Pendahuluan
• Epilepsi gangguan neurologis yang paling banyak terjadi,
0,5-2% dari populasi dunia.
• Manifestasi umum epilepsi : kejang
• Kejang ditandai dengan perubahan eksitabilitas (rangsangan)
neuron yang secara penting dibentuk oleh dua faktor utama :
• 1. keseimbangan input sinaps dari sel tetangga melalui
jaringan transmisi kimiawi (melalui ligan gated ion channels
reseptor G-protein-metabotropic)
• 2. sifat electrogenic intrinsik neuron masing-masing
• Faktor-faktor eksitabilitas fisiologis berperan dalam
hipereksitabilitas selama terjadi kejang pada epilepsi.
• Perangsangan maupun penghambatan neurotransmitter serta
voltage gated channels  menunjukkan terjadinya kejang
seperti aktivitas chemoconvulsant akut dalam irisan otak
tikus dan in vivo
• pengobatan kejang dan epilepsi banyak memfokuskan pada
saluran dan reseptor yang penting untuk inisiasi dan
penyebaran aktivitas kejang  VGIC
VOLTAGE GATED SODIUM CHANNEL
(VGSC)
 Voltage Gated ion Channel Genes Bearing
Mutations which have been Linked to Inherited
Epilepsy
Voltage-gated ion Gene name Syndrome
channel family
Potassium channels KCNQ2 BFNC
KCNQ3 BFNC
KCNQ3 JME
Sodium channels SCN1A GEFS+
SCN1A SMEI
SCN2A GEFS+
SCN2A BFNIC
SCN1B GEFS+
Calcium channels CACNA1A IGE

CACNA1H CAE
Fig. (1). (A) Structures of anticonvulsant drugs that act upon VGSCs.
(B) Diagram of the subunit structure of VGSC a and b subunits
showing the pore forming region, the voltage sensor and inactivation gate.
(C) Gating conformations of the voltage gated subunit.
DRUGS ACTING UPON VGSCs

(A) Sustained repetitive firing in current clamped cultured rat cortical neurons evoked
by somatic current injection. The PKC activator OAG (20mM) markedly reduces the
frequency of action potentials within the burst.
(B) Sodium currents from voltage clamped
mouse N1E-115 neuroblastoma cells are attenuated by application of 10mM OAG for
five minutes. Cells were voltage clamped at –100mV and test pulses were delivered to
0mV.
 STRUCTURE, FUNCTION AND ANTICONVULSANT
PHARMACOLOGY OF VOLTAGE GATED
CALCIUM CHANNELS

(A)Structures of anticonvulsant drugs acting at VGCCs.

(B)(B) Diagram of the subunit structure of the VGCC a subunit and the
accessory b, a2 and d subunits
(A) Postsynaptic responses to exogenously applied glutamate (1mM) and glycine (1mM) to whole cell
patch clamped dorsal root neurons. Gabapentin (1mM) does not significantly effect the amplitude or
duration of either the evoked excitatory or inhibitory currents.
(B) AMPA-EPSCs and GLY-IPSCs evoked by extracellular stimulation are significantly attenuated by
gabapentin (1mM) when N-type channels are blocked but not when P/Q-type channels are blocked.
This demonstrates gabapentin is able to preferentially block P/Q-type calcium channels in sensory
neurons.
STRUCTURE, FUNCTION AND ANTICONVULSANT
PHARMACOLOGY OF VOLTAGE GATED POTASSIUM
CHANNELS

(A) Structures of anticonvulsant drugs

acting at VGKCs.
(B) Diagram showing the structure of
potassium channel a subunits
including the voltage gated (Kv), KCNQ and
the twin pore KCNK type channels.
(C) Differences in subunit composition of
complete ionchannels. Na+ and Ca2+
channels are homomers comprising a single
a subunit whilst potassium channels are
formed by heteromeric
assembly of four smaller a subunits.
The anticonvulsant agent retigabine is mechanistically novel. It produces (A) a
concentration dependent increase in potassium conductance through KNCQ2/KNCQ3
heteromers expressed in CHO cells by directly opening the channel. (B) Retigabine also
shifts the voltage dependence of activation to more negative potentials in a reversible
fashion. This results in the cellular potential being taken further from the threshold
potential for spike firing
 KESIMPULAN
• Voltage Gated Ion Channels dapat dapat berperan penting pada
pengobatan epilepsi.
• Satu persatu perusahaan farmasi multinasional besar menarik
diri dari penemuan obat epilepsi  karena biaya
pengembangan mahal dan waktu yang lama  merugikan
banyak pasien kejadian kematian mendadak pada pasien
(Sudden Death In Epilepsy Patients, SUDEP)  butuh
pengembangan obat baru.
• Para analis pasar banyak yang mengabaikan janji keamanan
obat neuropatik nyeri  banyak antikonvulsan berlisensi
memiliki efek samping nyata : berupa sedasi, gangguan hati
fungsi dan serius diskrasia darah.
• Gabapentin telah menjadi goldstandard dalam pengobatan
pasca-herpes dan neuralgia trigeminal.
• NIH di Amerika Serikat terus mendanai penelitian penemuan
obat epilepsi dan nampaknya obat baru di masa depan akan
didominasi golongan superfamilies dari ion selective pores.