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Open AccessArticle

The Novel Direct Modulatory Effects of Perampanel, an Antagonist of AMPA Receptors, on Voltage-Gated Sodium and M-type Potassium Currents

1
Department of Pediatrics, Chi-Mei Medical Center, Tainan 710, Taiwan
2
Department of Neurology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan 701, Taiwan
3
Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
4
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
5
Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
*
Authors to whom correspondence should be addressed.
Biomolecules 2019, 9(10), 638; https://doi.org/10.3390/biom9100638
Received: 14 October 2019 / Accepted: 20 October 2019 / Published: 22 October 2019
Perampanel (PER) is a selective blocker of AMPA receptors showing efficacy in treating various epileptic disorders including brain tumor-related epilepsy and also potential in treating motor neuron disease. However, besides its inhibition of AMPA-induced currents, whether PER has any other direct ionic effects in different types of neurons remains largely unknown. We investigated the effects of PER and related compounds on ionic currents in different types of cells, including hippocampal mHippoE-14 neurons, motor neuron-like NSC-34 cells and U87 glioma cells. We found that PER differentially and effectively suppressed the amplitude of voltage-gated Na+ currents (INa) in mHippoE-14 cells. The IC50 values required to inhibit peak and late INa were 4.12 and 0.78 μM, respectively. PER attenuated tefluthrin-induced increases in both amplitude and deactivating time constant of INa. Importantly, PER also inhibited the amplitude of M-type K+ currents (IK(M)) with an IC50 value of 0.92 μM. The suppression of IK(M) was attenuated by the addition of flupirtine or ZnCl2 but not by L-quisqualic acid or sorafenib. Meanwhile, in cell-attached configuration, PER (3 μM) decreased the activity of M-type K+ channels with no change in single-channel conductance but shifting the activation curve along the voltage axis in a rightward direction. Supportively, PER suppressed IK(M) in NSC-34 cells and INa in U87 glioma cells. The inhibitory effects of PER on both INa and IK(M), independent of its antagonistic effect on AMPA receptors, may be responsible for its wide-spectrum of effects observed in neurological clinical practice. View Full-Text
Keywords: perampanel; M-type K+ current; Na+ current; hippocampal cell; motor neuron; glioma cell perampanel; M-type K+ current; Na+ current; hippocampal cell; motor neuron; glioma cell
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Lai, M.-C.; Tzeng, R.-C.; Huang, C.-W.; Wu, S.-N. The Novel Direct Modulatory Effects of Perampanel, an Antagonist of AMPA Receptors, on Voltage-Gated Sodium and M-type Potassium Currents. Biomolecules 2019, 9, 638.

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