Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca²⁺-Activated K⁺ Currents While Inhibiting Voltage-Gated Na⁺ Currents (2023)

Lai, M. C., Wu, S. N. (2022). Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents. International journal of molecular sciences, 23(22), [13677]. https://doi.org/10.3390/ijms232213677

Lai, Ming Chi ; Wu, Sheng Nan ; Huang, Chin Wei. / Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents. In: International journal of molecular sciences. 2022 ; Vol. 23, No. 22.

@article{91244d0854204959bae73534c0f383ac,

title = "Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents",

abstract = "Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels{\textquoteright} activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.",

author = "Lai, {Ming Chi} and Wu, {Sheng Nan} and Huang, {Chin Wei}",

note = "Funding Information: This research was funded by grants from the Ministry of Science and Technology, Taiwan (MOST-109-2314-B-006-034-MY3, MOST-111-2314-B-006-103-MY2). Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = nov,

doi = "10.3390/ijms232213677",

language = "English",

volume = "23",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "22",

}

Lai, MC, Wu, SN 2022, 'Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents', International journal of molecular sciences, vol. 23, no. 22, 13677. https://doi.org/10.3390/ijms232213677

Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents. / Lai, Ming Chi; Wu, Sheng Nan; Huang, Chin Wei.

In: International journal of molecular sciences, Vol. 23, No. 22, 13677, 11.2022.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents

AU - Lai, Ming Chi

AU - Wu, Sheng Nan

AU - Huang, Chin Wei

N1 - Funding Information:This research was funded by grants from the Ministry of Science and Technology, Taiwan (MOST-109-2314-B-006-034-MY3, MOST-111-2314-B-006-103-MY2).Publisher Copyright:© 2022 by the authors.

PY - 2022/11

Y1 - 2022/11

N2 - Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels’ activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.

AB - Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels’ activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.

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U2 - 10.3390/ijms232213677

DO - 10.3390/ijms232213677

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AN - SCOPUS:85142843537

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JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

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ER -

Lai MC, Wu SN, Huang CW. Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents. International journal of molecular sciences. 2022 Nov;23(22):13677. doi: 10.3390/ijms232213677