Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds

Xiong, Qiaojie; Gao, Zhaobing; Wang, Wei; Li, Min

doi:10.1016/j.tips.2007.11.010

Cited by 98 publications

(105 citation statements)

References 81 publications

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“…It was also proved that M-like currents are inhibited by activation of muscarinic receptors [84]. On the other hand, synthetic activators of K V 7 seem to cause conformational changes leading to channel opening by direct binding to the protein [82].…”

Section: Epilepsymentioning

confidence: 98%

“…Additional residues have also been found as affected by retigabine, like glycine residue in S6 [82].…”

Section: Retigabine (Rtg; Ezogabine)mentioning

confidence: 99%

“…K + currents occurring while opening the channels take part in reducing membrane excitability, thus VGKCs openers are of interest as antiepileptic drugs [82]. The especially interesting group of potassium channels while considering therapy of epilepsy is K V 7 (KNCQ) family or sometimes even more specified K V 7.2 and/or K V 7.3.…”

Section: Epilepsymentioning

confidence: 99%

“…Retigabine is thought to bind selectively to K V 7.2 -K V 7.5 channels, shifting the current-voltage curve to the left, which results that the channels open at more hyperpolarized membrane potentials [101]. The lack of RTG effect on K V 7.1 may be due to inefficient binding, which, however, has not been proved [82]. It increased the rate of channels activation while tested in Xenopus oocytes expressing KCNQ2 [102].…”

Section: Retigabine (Rtg; Ezogabine)mentioning

confidence: 99%

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Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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Section: Epilepsymentioning

confidence: 98%

“…Additional residues have also been found as affected by retigabine, like glycine residue in S6 [82].…”

Section: Retigabine (Rtg; Ezogabine)mentioning

confidence: 99%

Section: Epilepsymentioning

confidence: 99%

Section: Retigabine (Rtg; Ezogabine)mentioning

confidence: 99%

See 2 more Smart Citations

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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show abstract

“…KCNQ2 and KCNQ3 form heterotetramers in the neurons and mediate the M current, a potassium current could be inhibited by activation of muscarinic receptor. Inhibition of the M current by a mutation of KCNQ2 or KCNQ3 can result in various pathologies including benign familial neonatal convulsion, a form of neuronal hyperexcitibility [16][17][18] . The importance of Kv1.2 channels in controlling neuronal excitability has been demonstrated by the observation that Kv1.x (Kv1.1 and Kv1.2) channel-inhibiting venom toxins induce seizures in rodents [19] .…”

Section: Inhibition Of Herg Channel By Dc031050mentioning

confidence: 99%

Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels

Sun

Zhou

et al. 2012

Acta Pharmacol Sin

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Aim: This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels. Methods: Human ether-à-go-go related gene (hERG), KCNQ and Kv1.2 channels were expressed in CHO cells. The delayed rectifier potassium current (I K ) was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-100 Rapid Solution Changer. Results: Both DC031050 and dofetilide potently inhibited hERG currents with IC 50 values of 2.3±1.0 and 17.9±1.2 nmol/L, respectively. DC031050 inhibited the I K current with an IC 50 value of 2.7±1.5 μmol/L, which was >1000 times the concentration required to inhibit hERG current. DC031050 at 3 μmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of I K , or the rate of I K from inactivation. Intracellular application of DC031050 (5 μmol/L) was insufficient to inhibit I K . DC031050 up to 10 μmol/L had no effects on KCNQ2 and Kv1.2 channel currents. Conclusion: DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.

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Mechanisms of Epileptogenesis

Avanzini¹,

Franceschetti²

2015

The Treatment of Epilepsy

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Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds

Cited by 98 publications

References 81 publications

Ion Channels as Drug Targets in Central Nervous System Disorders

Ion Channels as Drug Targets in Central Nervous System Disorders

Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels

Mechanisms of Epileptogenesis

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