Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice

Oh, Hyoseon; Lee, Suho; Oh, Yusang; Kim, Seongbin; Kim, Young Seo; Yang, Yeji; Choi, Woochul; Yoo, Ye-Eun; Cho, Heejin; Lee, Seung-Joon; Yang, Esther; Koh, Wuhyun; Won, Woojin; Kim, Ryunhee; Lee, C. Justin; Kim, H.; Kang, Hyojin; Kim, Jin Young; Ku, Taeyun; Paik, Se-Bum; Kim, Eunjoon

doi:10.1038/s41467-023-39203-z

Cited by 4 publications

(1 citation statement)

References 62 publications

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“…In addition to the above-mentioned activities, LSs have also been reported to inhibit potassium ions, regulate metabolism, and analgesic activities. The abnormal function of potassium channels has been implicated in atrial fibrillation, 226 epilepsy, 227 and Alzheimer's disease, 228,229 and the effects of LSs on potassium channels have been discovered in recent years. Chlorahololides A ( 188 ) and B ( 229 ) exhibited potent inhibition on the delayed rectifier K + current, suggesting that LS can regulate body homeostasis by inhibiting K + efflux.…”

Section: Biological Activitiesmentioning

confidence: 99%

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

Luo,

Zhang,

Tang

et al. 2024

Nat. Prod. Rep.

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Section: Biological Activitiesmentioning

confidence: 99%

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

Luo,

Zhang,

Tang

et al. 2024

Nat. Prod. Rep.

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Pathogenic gating pore current conducted by autism-related mutations in the Na _V 1.2 brain sodium channel

Eltokhi,

Lundstrom,

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ /K V 7 potassium channel cause gating pore currents (I gp ) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A /Na V 1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of Na V 1.2 caused I gp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective I gp . These potentially pathogenic I gp were exacerbated by the absence of the extracellular Mg 2+ and Ca 2+ . In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward I gp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.

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Neuroprotective effects, mechanisms of action and therapeutic potential of the Kv7/KCNQ channel opener QO-83 in ischemic stroke

Zhang,

Tian,

Zhang

et al. 2024

Preprint

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Ischemic stroke is a worldwide disease with high mortality and morbidity. Kv7/KCNQ channels are key modulators of neuronal excitability and microglia function, and activation of Kv7/KCNQ channels has emerged as a potential therapeutic avenue for ischemic stroke. In the present study, we focused on a new Kv7/KCNQ channel opener QO-83 on the stroke outcomes and its therapeutic potential. Transient or distal middle cerebral artery occlusion model was established with C57 mouse to evaluate the role of QO-83. Solitary dose of QO-83 contributes to the microglia inhibition and fibrotic scar mitigation post stroke. QO83 shows prominent effect on reducing infarction area, alleviating cerebral edema, maintaining blood-brain barrier integrity, and enhancing neurogenesis. Single-nucleus RNA sequencing unveils neuroprotection and specific microglial subclusters influenced by QO-83. More importantly, QO83 shows promise in enhancing survival rates with dose dependence. Notably, these protective effects extend beyond the 4–6 h post-reperfusion window. Additionally, continuous dosing of QO-83 correlates with enhanced cognition. In conclusion, this study highlights QO-83 as a protective agent against ischemic brain injury, showcasing its multifaceted effects and potential as a therapeutic strategy.

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Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice

Cited by 4 publications

References 62 publications

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

Pathogenic gating pore current conducted by autism-related mutations in the Na _V 1.2 brain sodium channel

Neuroprotective effects, mechanisms of action and therapeutic potential of the Kv7/KCNQ channel opener QO-83 in ischemic stroke

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Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice

Cited by 4 publications

References 62 publications

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

Pathogenic gating pore current conducted by autism-related mutations in the Na V 1.2 brain sodium channel

Neuroprotective effects, mechanisms of action and therapeutic potential of the Kv7/KCNQ channel opener QO-83 in ischemic stroke

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Pathogenic gating pore current conducted by autism-related mutations in the Na _V 1.2 brain sodium channel