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PubMed1999

Idiopathic epilepsies with a monogenic mode of inheritance.

Idiopathic epilepsies account for approximately 40% of all epileptic diseases. For a long time, it has been known that genetic factors play a major role in the etiology of these diseases. Although oligogenic or polygenic inheritance is suspected in most of the common syndromes, a few rare idiopathic epilepsies are single-gene disorders. They offer a chance to identify candidate genes that also may be involved in epilepsies with complex inheritance. In recent years, major progress has been made regarding the analysis of genetic factors in idiopathic epilepsy. For the first time, gene defects could be linked to two idiopathic epilepsies. Mutations in the CHRNA4 gene, which codes for the alpha4 subunit of the neuronal nicotinic acetylcholine receptor, lead to autosomal dominant nocturnal frontal lobe epilepsy, a rare idiopathic partial epilepsy syndrome. Two highly homologous voltage-gated potassium channels, KCNQ2 and KCNQ3, were found to be mutated in benign familial neonatal convulsions.

Australia↗
PubMed2000

Differential tetraethylammonium sensitivity of KCNQ1-4 potassium channels.

In Shaker-group potassium channels the presence of a tyrosine residue, just downstream of the pore signature sequence GYG, determines sensitivity to tetraethylammonium (TEA). The KCNQ family of channels has a variety of amino acid residues in the equivalent position. We studied the effect of TEA on currents generated by KCNQ homomers and heteromers expressed in CHO cells. We used wild-type KCNQ1-4 channels and heteromeric KCNQ2/3 channels incorporating either wild-type KCNQ3 subunits or a mutated KCNQ3 in which tyrosine replaced threonine at position 323 (mutant T323Y). IC50 values were (mM): KCNQ1, 5.0; KCNQ2, 0.3; KCNQ3, > 30; KCNQ4, 3.0; KCNQ2 + KCNQ3, 3.8; and KCNQ2 + KCNQ3(T323Y), 0.5. While the high TEA sensitivity of KCNQ2 may be conferred by a tyrosine residue lacking in the other channels, the intermediate TEA sensitivity of KCNQ1 and KCNQ4 implies that other residues are also important in determining TEA block of the KCNQ channels.

Amino Acid Substitution↗
PubMed2003

A carboxy-terminal domain determines the subunit specificity of KCNQ K+ channel assembly.

Mutations in KCNQ K(+) channel genes underlie several human pathologies. KCNQ alpha-subunits form either homotetramers or hetero-oligomers with a restricted subset of other KCNQ alpha-subunits or with KCNE beta-subunits. KCNQ1 assembles with KCNE beta-subunits but not with other KCNQ alpha-subunits. By contrast, KCNQ3 interacts with KCNQ2, KCNQ4 and KCNQ5. Using a chimaeric strategy, we show that a cytoplasmic carboxy-terminal subunit interaction domain (sid) suffices to transfer assembly properties between KCNQ3 and KCNQ1. A chimaera (KCNQ1-sid(Q3)) carrying the si domain of KCNQ3 within the KCNQ1 backbone interacted with KCNQ2, KCNQ3 and KCNQ4 but not with KCNQ1. This interaction was shown by enhancement of KCNQ2 currents, testing for dominant-negative effects of pore mutants, determining its effects on surface expression and co-immunoprecipitation experiments. Conversely, a KCNQ3-sid(Q1) chimaera no longer affects KCNQ2 but interacts with KCNQ1. We conclude that the si domain suffices to determine the subunit specificity of KCNQ channel assembly.

Amino Acid Sequence↗
PubMed2001

KCNQ potassium channels: physiology, pathophysiology, and pharmacology.

KCNQ genes encode a growing family of six transmembrane domains, single pore-loop, K(+) channel alpha-subunits that have a wide range of physiological correlates. KCNQ1 (KvLTQ1) is co-assembled with the product of the KCNE1 (minimal K(+)-channel protein) gene in the heart to form a cardiac-delayed rectifier-like K(+) current. Mutations in this channel can cause one form of inherited long QT syndrome (LQT1), as well as being associated with a form of deafness. KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K(+) current present in colonic crypt cells. KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current; mutations in these genes may cause an inherited form of juvenile epilepsy. The KCNQ4 gene is thought to encode the molecular correlate of the I(K,n) in outer hair cells of the cochlea and I(K,L) in Type I hair cells of the vestibular apparatus, mutations in which lead to a form of inherited deafness. The recently identified KCNQ5 gene is expressed in brain and skeletal muscle, and can co-assemble with KCNQ3, suggesting it may also play a role in the M-current heterogeneity. This review will set this family of K(+) channels amongst the other known families. It will highlight the genes, physiology, pharmacology, and pathophysiology of this recently discovered, but important, family of K(+) channels.

Animals↗
PubMed2004

[Genetic background of epilepsies].

In this article we review epilepsies with monogenic inheritance. Most of these diseases are caused by abnormal function of ligand- and voltage gated ion channels caused by a genetic defect, therefore belonging to the channelopathies. From the inherited epilepsies the genetics of the autosomal dominant partial epilepsies is clarified the best. Mutations of the nicotinic acetylcholine receptor subunits are found in familial nocturnal frontal lobe epilepsy, while defects in the voltage gated potassium channels (KCNQ2 and KCNQ3) have been identified in benign familial neonatal convulsions. Familial temporolateral epilepsy was associated with mutations of a tumor suppressor gene. From the generalized epilepsies, the syndrome of generalized epilepsy with febrile seizures plus (GEFS+) can be caused by mutations of the sodium channel subunits and of the GABAA receptor subunits. These important results would probably lead to new findings in the genetics of the more common forms of idiopathic generalized epilepsies, which have presumed polygenic origin. Although without definite conclusions, sodium channel and GABA receptor dysfunction is presumed. The accumulated knowledge about channelopathies enables insight to the cellular mechanism of epileptogenesis as well.

Chromosomes, Human, X↗
PubMed2006

Structural determinants of M-type KCNQ (Kv7) K+ channel assembly.

The ability of KCNQ (Kv7) channels to form hetero-oligomers is of high physiological importance, because heteromers of KCNQ3 with KCNQ2 or KCNQ5 underlie the neuronal M-current, which modulates neuronal excitability. In KCNQ channels, we recently identified a C-terminal subunit interaction (si) domain that determines their subunit-specific assembly. Within this si domain, there are two motifs that comprise approximately 30 amino acid residues each and that exhibit a high probability for coiled-coil formation. Transfer of the first or the second coiled-coil (TCC) domain from KCNQ3 into the KCNQ1 scaffold resulted in chimeras KCNQ1(TCC1)Q3 and KCNQ1(TCC2)Q3, both of which coimmunoprecipitated with KCNQ2. However, only KCNQ1(TCC2)Q3 enhanced KCNQ2 currents and surface expression or exerted a strong dominant-negative effect on KCNQ2. Deletion of TCC2 within KCNQ2 yielded functional homomeric channels but prevented the current augmentation measured after coexpression of KCNQ2 and KCNQ3. In contrast, deleting TCC1 within KCNQ2 did not give functional homomeric KCNQ2 or heteromeric KCNQ2/KCNQ3 channels. Mutations that disrupted the predicted coiled-coil structure of TCC1 in KCNQ2 or KCNQ3 abolished channel activity after expressing these constructs singly or in combination, whereas helix-breaking mutations in TCC2 of KCNQ2 gave functional homomeric channels but prevented the heteromerization with KCNQ3. In contrast, KCNQ3 carrying a coiled-coil disrupting mutation in TCC2 hetero-oligomerized with KCNQ2. Our data suggest that the TCC1 domains of KCNQ2 and KCNQ3 are required to form functional homomeric as well as heteromeric channels, whereas both TCC2 domains facilitate an efficient transport of heteromeric KCNQ2/KCNQ3 channels to the plasma membrane.

Amino Acid Sequence↗
PubMed2004

Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent.

The cysteine-modifying reagent N-ethylmaleimide (NEM) is known to augment currents from native M-channels in sympathetic neurons and cloned KCNQ2 channels. As a probe for channel function, we investigated the mechanism of NEM action and subunit specificity of cloned KCNQ2-5 channels expressed in Chinese hamster ovary cells at the whole-cell and single-channel levels. Biotinylation assays and total internal reflection fluorescence microscopy indicated that NEM action is not caused by increased trafficking of channels to the membrane. At saturating voltages, whole-cell currents of KCNQ2, KCNQ4, and KCNQ5 but not KCNQ3 were augmented threefold to fourfold by 50 microm NEM, and their voltage dependencies were negatively shifted by 10-20 mV. Unitary conductances of KCNQ2 and KCNQ3 (6.2 and 8.5 pS, respectively) were much higher that those of KCNQ4 and KCNQ5 (2.1 and 2.2 pS, respectively). Surprisingly, the maximal open probability (P(o)) of KCNQ3 was near unity, much higher than that of KCNQ2, KCNQ4, and KCNQ5. NEM increased the P(o) of KCNQ2, KCNQ4, and KCNQ5 by threefold to fourfold but had no effect on their unitary conductances, suggesting that the increase in macroscopic currents can be accounted for by increases in P(o). Analysis of KCNQ3/4 chimeras determined the C terminus to be responsible for the differential maximal P(o), channel expression, and NEM action between the two channels. To further localize the site of NEM action, we mutated three cysteine residues in the C terminus of KCNQ4. The C519A mutation alone ablated most of the augmentation by NEM, suggesting that NEM acts via alkylation of this residue.

Animals↗
PubMed2003

Molecular determinants of KCNQ1 channel block by a benzodiazepine.

KCNQ1 channels underlie the slow delayed rectifier K+ current, mediate repolarization of cardiac action potentials, and are a potential therapeutic target for treatment of arrhythmia. (E)-(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2,4-dichlorophenyl)-2-propenamide [L-735821 (L-7)] is a potent blocker of KCNQ1 channels. Here we describe the structural determinants of KCNQ1 that are critical for high-affinity block by L-7 using site-directed mutagenesis to alter specific residues and voltage clamp to record channel currents in Xenopus laevis oocytes. Chimeric channels were constructed by combination of regions from L-7-sensitive KCNQ1 and L-7-insensitive KCNQ2 channel subunits. This approach localized the drug interaction site to the pore and S6 domains of KCNQ1. Substitution of single amino acids identified Thr-312 of the pore domain and Ile-337, Phe-339, Phe-340, and Ala-344 of the S6 domain as the most important molecular determinants of channel block. Some mutations also altered the inactivation properties of KCNQ1, but there was no correlation between extent of inactivation and sensitivity to block by L-7. Modeling was used to simulate the docking of L-7 to the KCNQ1 channel pore. The docking was consistent with our experimental data and predicts that L-7 blocks K+ conductance by physically precluding the occupancy of a K+ ion to a pore helix-coordinated site within the central hydrated cavity, a crucial step in ion permeation.

Amino Acid Sequence↗
PubMed2004

Dual phosphorylations underlie modulation of unitary KCNQ K(+) channels by Src tyrosine kinase.

Src tyrosine kinase suppresses KCNQ (M-type) K(+) channels in a subunit-specific manner representing a mode of modulation distinct from that involving G protein-coupled receptors. We probed the molecular and biophysical mechanisms of this modulation using mutagenesis, biochemistry, and both whole-cell and single channel modes of patch clamp recording. Immunoprecipitation assays showed that Src associates with KCNQ2-5 subunits but phosphorylates only KCNQ3-5. Using KCNQ3 as a background, we found that mutation of a tyrosine in the amino terminus (Tyr-67) or one in the carboxyl terminus (Tyr-349) abolished Src-dependent modulation of heterologously expressed KCNQ2/3 heteromultimers. The tyrosine phosphorylation was much weaker for either the KCNQ3-Y67F or KCNQ3-Y349F mutants and wholly absent in the KCNQ3-Y67F/Y349F double mutant. Biotinylation assays showed that Src activity does not alter the membrane abundance of channels in the plasma membrane. In recordings from cell-attached patches containing a single KCNQ2/3 channel, we found that Src inhibits the open probability of the channels. Kinetic analysis was consistent with the channels having two discrete open times and three closed times. Src activity reduced the durations of the longest open time and lengthened the longest closed time of the channels. The implications for the mechanisms of channel regulation by the dual phosphorylations on both channel termini are discussed.

Animals↗
PubMed2005

The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate.

Retigabine (RTG) is an anticonvulsant drug with a novel mechanism of action. It activates neuronal KCNQ-type K(+) channels by inducing a large hyperpolarizing shift of steady-state activation. To identify the structural determinants of KCNQ channel activation by RTG, we constructed a set of chimeras using the neuronal K(v)7.2 (KCNQ2) channel, which is activated by RTG, and the cardiac K(v)7.1 (KCNQ1) channel, which is not affected by this drug. Substitution of either the S5 or the S6 segment in K(v)7.2 by the respective parts of K(v)7.1 led to a complete loss of activation by RTG. Trp236 in the cytoplasmic part of S5 and the conserved Gly301 in S6 (K(v)7.2), considered as the gating hinge (Ala336 in K(v)7.1), were found to be crucial for the RTG effect: mutation of these residues could either knockout the effect in K(v)7.2 or restore it partially in K(v)7.1/K(v)7.2 chimeras. We propose that RTG binds to a hydrophobic pocket formed upon channel opening between the cytoplasmic parts of S5 and S6 involving Trp236 and the channel's gate, which could well explain the strong shift in voltage-dependent activation.

Amino Acid Sequence↗
PubMed2005

Cholinergic suppression of KCNQ channel currents enhances excitability of striatal medium spiny neurons.

In response to glutamatergic synaptic drive, striatal medium spiny neurons in vivo transition to a depolarized "up state" near spike threshold. In the up state, medium spiny neurons either depolarize enough to spike or remain below spike threshold and are silent before returning to the hyperpolarized "down state." Previous work has suggested that subthreshold K+ channel currents were responsible for this dichotomous behavior, but the channels giving rise to the current and the factors determining its engagement have been a mystery. To move toward resolution of these questions, perforated-patch recordings from medium spiny neurons in tissue slices were performed. K+ channels with pharmacological and kinetic features of KCNQ channels potently regulated spiking at up-state potentials. Single-cell reverse transcriptase-PCR confirmed the expression of KCNQ2, KCNQ3, and KCNQ5 mRNAs in medium spiny neurons. KCNQ channel currents in these cells were potently reduced by M1 muscarinic receptors, because the effects of carbachol were blocked by M1 receptor antagonists and lost in neurons lacking M1 receptors. Reversal of the modulation was blocked by a phosphoinositol 4-kinase inhibitor, indicating a requirement for phosphotidylinositol 4,5-bisphosphate resynthesis for recovery. Inhibition of protein kinase C reduced the efficacy of the muscarinic modulation. Finally, acceleration of cholinergic interneuron spiking with 4-aminopyridine mimicked the effects of exogenous agonist application. Together, these results show that KCNQ channels are potent regulators of the excitability of medium spiny neurons at up-state potentials, and they are modulated by intrastriatal cholinergic interneurons, providing a mechanistic explanation for variability in spiking during up states seen in vivo.

4-Aminopyridine↗
PubMed2004

Modulation of KCNQ4 channel activity by changes in cell volume.

KCNQ4 channels expressed in HEK 293 cells are sensitive to cell volume changes, being activated by swelling and inhibited by shrinkage, respectively. The KCNQ4 channels contribute significantly to the regulatory volume decrease (RVD) process following cell swelling. Under isoosmotic conditions, the KCNQ4 channel activity is modulated by protein kinases A and C, G protein activation, and a reduction in the intracellular Ca2+ concentration, but these signalling pathways are not responsible for the increased channel activity during cell swelling.

Calcium↗
PubMed2006

The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels.

The family of Kv7 (KCNQ) potassium channels consists of five members. Kv7.2 and 3 are the primary molecular correlates of the M-current, but also Kv7.4 and Kv7.5 display M-current characteristics. M-channel modulators include blockers (e.g., linopirdine) for cognition enhancement and openers (e.g., retigabine) for treatment of epilepsy and neuropathic pain. We investigated the effect of a Bristol-Myers Squibb compound (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide [(S)-1] on cloned human Kv7.1-5 potassium channels expressed in Xenopus laevis oocytes. Using two-electrode voltage-clamp recordings we found that (S)-1 blocks Kv7.1 and Kv7.1/KCNE1 currents. In contrast, (S)-1 produced a hyperpolarizing shift of the activation curve for Kv7.2, Kv7.2/Kv7.3, Kv7.4 and Kv7.5. Further, the compound enhanced the maximal current amplitude at all potentials for Kv7.4 and Kv7.5 whereas the combined activation/block of Kv7.2 and Kv7.2/3 was strongly voltage-dependent. The tryptophan residue 242 in S5, known to be crucial for the effect of retigabine, was also shown to be critical for the enhancing effect of (S)-1 and BMS204352. Furthermore, no additive effect on Kv7.4 current amplitude was observed when both retigabine and (S)-1 or BMS204352 were applied simultaneously. In conclusion, (S)-1 differentially affects the Kv7 channel subtypes and is dependent on a single tryptophan for the current enhancing effect in Kv7.4.

Acrylamides↗
PubMed2000

Dysfunction of M-channel enhances propagation of neuronal excitability in rat hippocampus monitored by multielectrode dish and microdialysis systems.

To explore the pathogenesis of benign familial neonatal convulsions (BFNC), we determined effects of KCNQ-related M-channels (KCNQ-channels) on hippocampal glutamate (Glu) and gamma-aminobutyric acid (GABA) releases using microdialysis, and propagation of evoked field-potentials (FP) using multielectrode (64-ch)-dish system as two-dimensional monitoring. KCNQ-channel inhibitor, Dup996, enhanced hippocampal K(+)-evoked Glu and GABA releases without affecting basal releases of them. Dup996 unaffected FP-amplitude, but enhanced FP-propagation. The GABA(A)-receptor antagonist, bicuculline, enhanced the stimulatory effects of Dup996 on FP-propagation, however, this stimulatory effects of Dup996 were abolished by the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/glutamate-receptor antagonist, DNQX. These results suggest that the occurrence of BFNC cannot be produced by KCNQ-channel dysfunction alone, but by reciprocal action between impaired KCNQ-channel and other unknown elements (possibly dysfunction of inhibitory neurotransmission system).

Action Potentials↗
PubMed2003

Phosphatidylinositol-4,5-bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K+ channels.

Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is a major signaling molecule implicated in the regulation of various ion transporters and channels. Here we show that PIP(2) and intracellular MgATP control the activity of the KCNQ1/KCNE1 potassium channel complex. In excised patch-clamp recordings, the KCNQ1/KCNE1 current decreased spontaneously with time. This rundown was markedly slowed by cytosolic application of PIP(2) and fully prevented by application of PIP(2) plus MgATP. PIP(2)-dependent rundown was accompanied by acceleration in the current deactivation kinetics, whereas the MgATP-dependent rundown was not. Cytosolic application of PIP(2) slowed deactivation kinetics and also shifted the voltage dependency of the channel activation toward negative potentials. Complex changes in the current characteristics induced by membrane PIP(2) was fully restituted by a model originally elaborated for ATP-regulated two transmembrane-domain potassium channels. The model is consistent with stabilization by PIP(2) of KCNQ1/KCNE1 channels in the open state. Our data suggest a striking functional homology between a six transmembrane-domain voltage-gated channel and a two transmembrane-domain ATP-gated channel.

Adenosine Triphosphate↗
PubMed2006

Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels.

To resolve the controversy about messengers regulating KCNQ ion channels during phospholipase C-mediated suppression of current, we designed translocatable enzymes that quickly alter the phosphoinositide composition of the plasma membrane after application of a chemical cue. The KCNQ current falls rapidly to zero when phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2 or PI(4,5)P2] is depleted without changing Ca2+, diacylglycerol, or inositol 1,4,5-trisphosphate. Current rises by 30% when PI(4,5)P2 is overproduced and does not change when phosphatidylinositol 3,4,5-trisphosphate is raised. Hence, the depletion of PI(4,5)P2 suffices to suppress current fully, and other second messengers are not needed. Our approach is ideally suited to study biological signaling networks involving membrane phosphoinositides.

Animals↗
PubMed2002

Molecular and functional characterization of ERG, KCNQ, and KCNE subtypes in rat stomach smooth muscle.

Contribution of K(+) channels derived from the expression of ERG, KCNQ, and KCNE subtypes, which are responsible for rapidly and slowly activating delayed rectifier K(+) currents (I(Kr) and I(Ks), respectively) in cardiac myocytes, to membrane currents was examined in stomach circular smooth muscle cells (SMCs). The region-qualified multicell RT-PCR showed that ERG1/KCNE2 transcripts were expressed in rat stomach fundus and antrum SMCs and that KCNQ1/KCNE1 transcripts were expressed in antrum but not fundus. Western blotting and immunocytochemical analyses indicate that ERG1 proteins were substantially expressed in both regions, whereas KCNE1 proteins were faintly expressed in antrum and not in fundus. Both I(Kr)- and I(Ks)-like currents susceptible to E-4031 and indapamide, respectively, were identified in circular SMCs of antrum but only I(Kr)-like current was identified in fundus. It is strongly suggested that I(Kr)- and I(Ks)-like currents functionally identified in rat stomach SMCs are attributable to the expression of ERG1/KCNE2 and KCNQ1/KCNE1, respectively. The membrane depolarization by 1 microM E-4031 indicates the contribution of K(+) channels encoded by ERG1/KCNE2 to the resting membrane potential in stomach SMCs.

Animals↗