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. 2020 Aug;61(8):1678-1690.
doi: 10.1111/epi.16592. Epub 2020 Jul 11.

Functional and behavioral signatures of Kv7 activator drug subtypes

Richard Kanyo  1 , Caroline K Wang  2 , Laszlo F Locskai  1 , Jingru Li  2 , W Ted Allison  1 , Harley T Kurata  2
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Functional and behavioral signatures of Kv7 activator drug subtypes

Richard Kanyo et al. Epilepsia. 2020 Aug.

Abstract

Objective: Voltage-gated potassium channels of the KCNQ (Kv7) family are targeted by a variety of activator compounds with therapeutic potential for treatment of epilepsy. Exploration of this drug class has revealed a variety of effective compounds with diverse mechanisms. In this study, we aimed to clarify functional criteria for categorization of Kv7 activator compounds, and to compare the effects of prototypical drugs in a zebrafish larvae model.

Methods: In vitro electrophysiological approaches with recombinant ion channels were used to highlight functional properties important for classification of drug mechanisms. We also benchmarked the effects of representative antiepileptic Kv7 activator drugs using behavioral seizure assays of zebrafish larvae and in vivo Ca2+ imaging with the ratiometric Ca2+ sensor CaMPARI.

Results: Drug effects on channel gating kinetics, and drug sensitivity profiles to diagnostic channel mutations, were used to highlight properties for categorization of Kv7 activator drugs into voltage sensor-targeted or pore-targeted subtypes. Quantifying seizures and ratiometric Ca2+ imaging in freely swimming zebrafish larvae demonstrated that while all Kv7 activators tested lead to suppression of neuronal excitability, pore-targeted activators (like ML213 and retigabine) strongly suppress seizure behavior, whereas ICA-069673 triggers a seizure-like hypermotile behavior.

Significance: This study suggests criteria to categorize antiepileptic Kv7 activator drugs based on their underlying mechanism. We also establish the use of in vivo CaMPARI as a tool for screening effects of anticonvulsant drugs on neuronal excitability in zebrafish. In summary, despite a shared ability to suppress neuronal excitability, our findings illustrate how mechanistic differences between Kv7 activator subtypes influence their effects on heteromeric channels and lead to vastly different in vivo outcomes.

Keywords: CaMPARI; Kv7 channel activator; epilepsy; potassium channel; retigabine; zebrafish.

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References

REFERENCES

    1. Miceli F, Soldovieri MV, Martire M, Taglialatela M. Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs. Curr Opin Pharmacol. 2008;8:65-74.
    1. Suh B-C, Inoue T, Meyer T, Hille B. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science. 2006;314:1454-7.
    1. Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H. The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol. 2005;67:1009-17.
    1. Miceli F, Soldovieri MV, Ambrosino P, Manocchio L, Mosca I, Taglialatela M. Pharmacological targeting of neuronal Kv7.2/3 channels: a focus on chemotypes and receptor sites. Curr Med Chem. 2018;25:2637-60.
    1. Wang AW, Yau MC, Wang CK, et al. Four drug-sensitive subunits are required for maximal effect of a voltage sensor-targeted KCNQ opener. J Gen Physiol. 2018;150:1432-43.

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