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

Epilepsy affects more than 0.5% of the world's population and has a large g enetic component(1). It is due to an electrical hyperexcitability in the ce ntral nervous system. Potassium channels are important regulators of electr ical signalling, and benign familial neonatal convulsions (BFNC), an autoso mal dominant epilepsy of infancy, is caused by mutations in the KCNQ2 or th e KCNQ3 potassium channel genes(2-4), 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 KCNQ 2/KCNQ3 potassium channels with currents that are at least tenfold larger t han 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 mutation s identified in BFNC pedigrees compromised the function of the respective s ubunits, but exerted no dominant-negative effect on KCNQ2/KCNQ3 heteromeric channels. We predict that a 25% loss of heteromeric KCNQ2/ KCNQ3-channel f unction is sufficient to cause the electrical hyperexcitability in BFNC, Dr ugs raising intracellular cAMP may prove beneficial in this form of epileps y.