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Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy

Abstract

Epilepsy affects more than 0.5% of the world's population and has a large genetic component1. It is due to an electrical hyperexcitability in the central nervous system. Potassium channels are important regulators of electrical signalling, and benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or the KCNQ3 potassium channel genes2,3,4. Here we show that KCNQ2 and KCNQ3 are distributed broadly in brain with expression patterns that largely overlap. Expression in Xenopus oocytes indicates the formation of heteromeric KCNQ2/KCNQ3 potassium channels with currents that are at least tenfold larger than those of the respective homomeric channels. KCNQ2/KCNQ3 currents can be increased by intracellular cyclic AMP, an effect that depends on an intact phosphorylation site in the KCNQ2 amino terminus. KCNQ2 and KCNQ3 mutations identified in BFNC pedigrees compromised the function of the respective subunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC. Drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.

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Figure 1: Partial alignment of KCNQ2 and KCNQ3 potassium channel subunits showing the newly identified KCNQ3 N terminus, the cAMP-dependent phosphorylation site (*) in KCNQ2, and the point mutations introduced here.
Figure 2: Expression patterns of KCNQ2 and KCNQ3.
Figure 3: Functional expression of KCNQ channels in Xenopus oocytes.
Figure 4: Effect of PKA on KCNQ2/KCNQ3 channels expressed in HEK293 cells.
Figure 5: Functional analysis of KCNQ2 and KCNQ3 mutations.

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Acknowledgements

We thank S. Fehr for the preparation of rat brain slices and the in situ hybridization, and T. Friedrich for comments on the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie to T.J.J.

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Correspondence to Thomas J. Jentsch.

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Schroeder, B., Kubisch, C., Stein, V. et al. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 396, 687–690 (1998). https://doi.org/10.1038/25367

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