Modulation of the heart's electrical properties by the anticonvulsant drug retigabine

Rubi, Lena; Kovar, Michael; Zebedin-Brandl, Eva; Koenig, Xaver; Dominguez-Rodriguez, Manuel; Todt, Hannes; Kubista, Helmut; Boehm, Stefan; Hilber, Karlheinz

doi:10.1016/j.taap.2017.06.018

Cited by 6 publications

(5 citation statements)

References 46 publications

(105 reference statements)

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“… Tykocki et al (2019) also suggested that retigabine may cause partial inhibition of the L-type Ca V channels in mouse DSM cells, consistent with prior findings ( Mani et al, 2013 ; Rubi et al, 2017 ). At 10 μM, retigabine weakly attenuated the mouse DSM inward voltage-gated Ca V current by ∼25% (from 8 to 6 pA/pF, evoked by the voltage step from −60 to +20 mV), while 60 mM KCl induced tonic contraction (primarily mediated via L-type Ca V channel activation) by ∼20% ( Tykocki et al, 2019 ).…”

Section: K V 7 Channel Functional Studies On Dsm Csupporting

confidence: 82%

“…Hence, future studies should address what may have been methodological issues and confirm the functional presence of K V 7 channels in mouse DSM cells using more precise patch-clamp protocols for recording native K V 7 channel currents. Tykocki et al (2019) also suggested that retigabine may cause partial inhibition of the L-type Ca V channels in mouse DSM cells, consistent with prior findings (Mani et al, 2013;Rubi et al, 2017). At 10 µM, retigabine weakly attenuated the mouse DSM inward voltage-gated Ca V current by ∼25% (from 8 to 6 pA/pF, evoked by the voltage step from −60 to +20 mV), while 60 mM KCl induced tonic contraction (primarily mediated via L-type Ca V channel activation) by ∼20% (Tykocki et al, 2019).…”

Section: Expression Of K V 7 Channel Subtypes In Dsm Whole-tissue Andsupporting

confidence: 80%

“…The mechanism involved remains to be elucidated; however, a direct effect on the heart is unlikely. When tested in guinea pig and human cardiomyocytes, retigabine induced a reduction rather than a prolongation of the action potential ( Rubi et al, 2017 ). Other limitations for retigabine and flupirtine are their non-selectivity among K V 7 channel subtypes (both are active at K V 7.2-K V 7.5 channels), and their relatively weak potency ( Miceli et al, 2008 , 2011 , 2018 ).…”

Section: K V 7 Channel Pharmacological Activation mentioning

confidence: 99%

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Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

Malysz

Petkov

2020

Front. Physiol.

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Relaxation and contraction of the urinary bladder smooth muscle, also known as the detrusor smooth muscle (DSM), facilitate the micturition cycle. DSM contractility depends on cell excitability, which is established by the synchronized activity of multiple diverse ion channels. K + channels, the largest family of channels, control DSM excitability by maintaining the resting membrane potential and shaping the action potentials that cause the phasic contractions. Among the members of the voltage-gated K + (K V) channel superfamily, K V type 7 (K V 7) channels-K V 7.1-K V 7.5 members encoded by KCNQ1-KCNQ5 genes-have been recently identified as functional regulators in various cell types including vascular, cardiac, and neuronal cells. Their regulatory roles in DSM, however, are just now emerging and remain to be elucidated. To address this gap, our research group has initiated the systematic investigation of human DSM K V 7 channels in collaboration with clinical urologists. In this comprehensive review, we summarize the current understanding of DSM Kv7 channels and highlight recent discoveries in the field. We describe K V 7 channel expression profiles at the mRNA and protein levels, and further elaborate on functional effects of K V 7 channel selective modulators on DSM excitability, contractility, and intracellular Ca 2+ dynamics in animal species along with in vivo studies and the limited data on human DSM. Within each topic, we highlight the main observations, current gaps in knowledge, and most pressing questions and concepts in need of resolution. We emphasize the lack of systematic studies on human DSM K V 7 channels that are now actively ongoing in our laboratory.

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Section: K V 7 Channel Functional Studies On Dsm Csupporting

confidence: 82%

Section: Expression Of K V 7 Channel Subtypes In Dsm Whole-tissue Andsupporting

confidence: 80%

Section: K V 7 Channel Pharmacological Activation mentioning

confidence: 99%

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Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

Malysz

Petkov

2020

Front. Physiol.

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“…The only AED with a novel mechanism of action is an FDA approved retigabine (or ezogabine) in 2011 that activates the voltage-gated Kv7/KCNQ/M-channels for the treatment of partial epilepsy (Weisenberg and Wong, 2011). Nevertheless, the antiepileptic drug retigabine was recently withdrawn from the market due to its metabolites causing side effects such as vision change and discoloration of the skin (Rubi et al, 2017). 6 Kv7/KCNQ/M-channels are a subfamily of voltage-gated K + channels with five members, Kv7.1-7.5 (Gutman et al, 2005;Brown and Passmore, 2009a;Greene and Hoshi, 2017).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Epileptogenesis and Cognitive Deficits by a Selective and Potent Kv7 Channel Opener in Rodent Models of Seizures

Zhuang

Liu

Zhi-yong

et al. 2022

J Pharmacol Exp Ther

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Targeting neuronal Kv7 channels by pharmacological activation has been proven to be an attractive therapeutic strategy for epilepsy. Here, we show that activation of Kv7 channels by an opener SCR2682 dose-dependently reduces seizure activity and severity in rodent models of epilepsy induced by a GABAa receptor antagonist pentylenetetrazole (PTZ), maximal electroshock and a glutamate receptor agonist kainic acid (KA). Electroencephalographic (EEG) recordings of rat cerebral cortex confirm that SCR2682 also decreases epileptiform discharges in KA-induced seizures.Nissl and NeuN staining further demonstrates that SCR2682 also protects neurons from injury induced by KA. In Morris water maze navigation and Y maze tests, SCR2682 improves PTZ-induced and KA-induced cognitive impairment. Taken together, our findings demonstrate that pharmacological activation of Kv7 by novel opener SCR2682 may hold promise for therapy of epilepsy with cognitive impairment.

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“…RTG can also activate all subtypes of the Kv7 family such as Kv7.2, Kv7.3, Kv7.4, Kv7.5, and Kv7.2/Kv7.3 channels, except Kv7.1, which is slightly inhibited by RTG (22). However, RTG renders adverse effects, including blue skin discoloration, retinal pigment abnormalities, and even cardiac arrhythmias (23)(24)(25), suggesting that a more specific Kv7 subtype activator is required for better efficacy and less toxicity.…”

mentioning

confidence: 99%

Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy

et al. 2019

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Voltage‐gated Kv7/KCNQ/M potassium channels play an essential role in the control of membrane potential and neuronal excitability. Activation of the neuronal Kv7/KCNQ/M‐current represents an attractive therapeutic strategy for treatment of hyperexcitability‐related neuropsychiatric disorders such as epilepsy, pain, and depression, which is an unmet medical need. In this study, we synthesized and characterized a novel compound, N‐(4‐(2‐bromo‐6,7‐dihydrothieno[3,2‐c]pyridin‐5(4H)‐yl)‐2,6‐dimethylphenyl)‐3,3‐dimethylbutanamide (SCR2682) 2,6‐dimethyl‐4‐(piperidin‐yl) phenyl)‐amide derivative, that exhibits selective and potent activation of neuronal Kv7/KCNQ/M‐channels. Whole‐cell patch‐clamp recordings of human embryonic kidney 293 cells expressing Kv7.2/Kv7.3 channels show that SCR2682 selectively activates the channel current in a dose‐dependent manner with an EC50 of 9.8 ± 0.4 nM, which is ∼100‐fold more potent than a U.S. Food and Drug Administration–approved antiepileptic drug (retigabine) for treatment of partial epilepsy. SCR2682 shifts voltage‐dependent activation of the Kv7.2/7.3 current toward more negative membrane potential, to about −37 mV (V1/2). SCR2682 also activates the native M‐current in rat hippocampal or cortical neurons, causing marked hyperpolarization and potent inhibition of neuronal firings. Mechanistically, mutating the tryptophan residue 236 located at the fifth transmembrane segment of Kv7.2 abolishes the chemical activation of the channel by SCR2682. Furthermore, intraperitoneal or intragastric administration of SCR2682 results in a dose‐dependent inhibition of seizures by maximal electroshock. Taken together, our findings demonstrate that a novel small molecule, SCR2682, selectively and potently activates neuronal Kv7 channels and reverses epileptic seizures in rodents. Thus, SCR2682 may warrant further evaluation for clinical development of antiepileptic therapy.—Zhang, F., Liu, Y., Tang, F., Liang, B., Chen, H., Zhang, H., Wang, K. Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy. FASEB J. 33, 9154–9166 (2019). http://www.fasebj.org

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Modulation of the heart's electrical properties by the anticonvulsant drug retigabine

Cited by 6 publications

References 46 publications

Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

Detrusor Smooth Muscle KV7 Channels: Emerging New Regulators of Urinary Bladder Function

Attenuation of Epileptogenesis and Cognitive Deficits by a Selective and Potent Kv7 Channel Opener in Rodent Models of Seizures

Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy

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