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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"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. "
[Show abstract][Hide abstract] ABSTRACT: Memories are thought to be sparsely encoded in neuronal networks, but little is known about why a given neuron is recruited or allocated to a particular memory trace. Previous research shows that in the lateral amygdala (LA), neurons with increased CREB are selectively recruited to a fear memory trace. CREB is a ubiquitous transcription factor implicated in many cellular processes. Which process mediates neuronal memory allocation? One hypothesis is that CREB increases neuronal excitability to bias neuronal recruitment, although this has not been shown experimentally. Here we use several methods to increase neuronal excitability and show this both biases recruitment into the memory trace and enhances memory formation. Moreover, artificial activation of these neurons alone is a sufficient retrieval cue for fear memory expression, showing that these neurons are critical components of the memory trace. These results indicate that neuronal memory allocation is based on relative neuronal excitability immediately before training. VIDEO ABSTRACT:
"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]. "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, EEG suppression-burst pattern (Ohtahara syndrome) and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy". In the present paper, we describe clinical, genetic and functional data from 17 patients/families whose electro-clinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three ins/del and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly-found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies. This article is protected by copyright. All rights reserved.
Human Mutation 12/2013; 35(3). DOI:10.1002/humu.22500 · 5.14 Impact Factor
"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. "
[Show abstract][Hide abstract] ABSTRACT: K(+) channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K(+) channels as primary targets of genetic variations or perturbations in K(+)-dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K(+) channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K(+) channels defects underlying distinct epilepsies as "K(+) channelepsies," and introduce a new nomenclature (e.g., Kx.y-channelepsy), following the widely used K(+) channel classification, which could be also adopted to easily identify other channelopathies involving Na(+) (e.g., Nav x.y-phenotype), Ca(2+) (e.g., Cav x.y-phenotype), and Cl(-) channels. Furthermore, we discuss novel genetic defects in K(+) channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K(+) channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.