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

Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Germany.
Nature (Impact Factor: 41.46). 01/1999; 396(6712):687-90. DOI: 10.1038/25367
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Epilepsy affects more than 0.5% of the world's population and has a large genetic component. 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 genes. 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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Available from: Valentin Stein, Feb 08, 2015
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    • "Two members of the voltagedependent K + family of channels, KCNQ2 and related KCNQ3, help mediate the AHP and function as molecular brakes on neuron firing (Delmas and Brown, 2005; Gu et al., 2005). Expression of a dominant-negative KCNQ2 mutant (hQ2-G279S; dnKCNQ2) coassembles with native KCNQ2/3 subunits, disrupts their function, and thereby increases neuronal excitability (Peters et al., 2005; Schroeder et al., 1998; Wuttke et al., 2007). We observed that LA neurons in adult mice endogenously express KCNQ2-containing channels (Figure 1C), suggesting that expression of the dnKCNQ2 construct could be a viable method for increasing excitability in LA neurons. "
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    • "All missense mutations and functional consequences have been studied for five of them; four of them (p.Glu299Lys, p.Asp305Gly, p.Trp309Arg, and p.Gly310Val) are located in the pore region of Q3 and the fifth one (p.Arg330Cys) immediately before S6. Functional analyses in Xenopus oocytes showed that Q3 subunits carrying the p.Gly310Val and p.Asp305Gly mutation caused a 20% and 40% reduction, respectively , in the maximal current of heteromeric Q2/Q3 channels [Schroeder et al., 1998; Singh et al., 2003], whereas the Q3 p.Trp309Arg mutation was found to reduce by over 60% the Q2/Q3 heteromeric channel currents in HEK293 cells, suggesting a dominant negative effect [Uehara et al., 2008; Sugiura et al., 2009]. "
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    • "Indeed, blockade of M-currents is associated with depolarization of the resting membrane potential, and generation of trains of action potentials (Brown and Adams, 1980; Delmas and Brown, 2005). Mutations in KCNQ2 or KCNQ3 cause a form of juvenile epilepsy called benign familial neonatal convulsions (Biervert et al., 1998; Charlier et al., 1998; Schroeder et al., 1998; Singh et al., 1998, Table 1). The clinical features of KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) are characterized by tonic or apneic episodes, focal clonic activity, or autonomic changes that start between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12 th month. "
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