Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In humans, mutations in the KCNQ2 or KCNQ3 potassium-channel genes are associated with an inherited epilepsy syndrome. We have studied the contribution of KCNQ/M-channels to the control of neuronal excitability by using transgenic mice that conditionally express dominant-negative KCNQ2 subunits in brain. We show that suppression of the neuronal M current in mice is associated with spontaneous seizures, behavioral hyperactivity and morphological changes in the hippocampus. Restriction of transgene expression to defined developmental periods revealed that M-channel activity is critical to the development of normal hippocampal morphology during the first postnatal weeks. Suppression of the M current after this critical period resulted in mice with signs of increased neuronal excitability and deficits in hippocampus-dependent spatial memory. M-current-deficient hippocampal CA1 pyramidal neurons showed increased excitability, reduced spike-frequency adaptation, attenuated medium afterhyperpolarization and reduced intrinsic subthreshold theta resonance. M channels are thus critical determinants of cellular and neuronal network excitability, postnatal brain development and cognitive performance.
 ...
PMID:Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. 1726 36

Epilepsy is caused by an electrical hyperexcitability in the CNS. Because K+ channels are critical for establishing and stabilizing the resting potential of neurons, a loss of K+ channels could support neuronal hyperexcitability. Indeed, benign familial neonatal convulsions, an autosomal dominant epilepsy of infancy, is caused by mutations in KCNQ2 or KCNQ3 K+ channel genes. Because these channels contribute to the native muscarinic-sensitive K+ current (M current) that regulates excitability of numerous types of neurons, KCNQ (Kv7) channel activators would be effective in epilepsy treatment. A compound exhibiting anticonvulsant activity in animal seizure models is retigabine. It specifically acts on the neuronally expressed KCNQ2-KCNQ5 (Kv7.2-Kv7.5) channels, whereas KCNQ1 (Kv7.1) is not affected. Using the differential sensitivity of KCNQ3 and KCNQ1 to retigabine, we constructed chimeras to identify minimal segments required for sensitivity to the drug. We identified a single tryptophan residue within the S5 segment of KCNQ3 and also KCNQ2, KCNQ4, and KCNQ5 as crucial for the effect of retigabine. Furthermore, heteromeric KCNQ channels comprising KCNQ2 and KCNQ1 transmembrane domains (attributable to transfer of assembly properties from KCNQ3 to KCNQ1) are retigabine insensitive. Transfer of the tryptophan into the KCNQ1 scaffold resulted in retigabine-sensitive heteromers, suggesting that the tryptophan is necessary in all KCNQ subunits forming a functional tetramer to confer drug sensitivity.
 ...
PMID:Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. 1590 87

Compounds that stimulate or inhibit M-channels (ie, voltage-gated potassium channels formed by KCNQ2, KCNQ3 and KCNQ5) have been evaluated in clinical trials for epilepsy, stroke and Alzheimer's disease. The importance of M-channel function in reducing neuronal excitability is underscored by the finding that KCNQ2/3 mutations causing mild reduction of M-channel activity are linked to neonatal epilepsy. M-channel openers decrease the hyperexcitability responsible for epileptic seizures, neuropathic pain and migraine. Conversely, M-channel blockers may enhance cognitive functions. The M-channel has thus emerged as a promising target for treating epilepsy, stroke, migraine, pain, dementia, anxiety and bipolar disorder.
 ...
PMID:A potassium channel, the M-channel, as a therapeutic target. 1604 66

The mutational analysis of potassium (KCNQ2, KCNQ3), sodium (SCN1A, SCN2A), and chloride (CLCN2) ion channels was performed in three children with typical features of the recently described syndrome of migrating partial seizures in infancy. Mutational analysis was performed by PCR and automatic sequencing. The coding regions, including the exon-intron boundaries, were amplified in the patients using appropriate primers sets. No mutations associated to migrating partial seizures have been found. Mutational screening of CLCN2 gene, revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. The same variation has been found in 38 out of 100 control alleles. The identification of the genetic basis of this new epileptic encephalopathy requires further studies that might be enforced by familial cases.
 ...
PMID:Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy. 1616 94

The idiopathic generalized epilepsies (IGEs) are considered to be primarily genetic in origin. They encompass a number of rare mendelian or monogenic epilepsies and more common forms which are familial but manifest as complex, non-mendelian traits. Recent advances have demonstrated that many monogenic IGEs are ion channelopathies. These include benign familial neonatal convulsions due to mutations in KCNQ2 or KCNQ3, generalized epilepsy with febrile seizures plus due to mutations in SCN1A, SCN2A, SCN1B, and GABRG2, autosomal-dominant juvenile myoclonic epilepsy (JME) due to a mutation in GABRA1 and mutations in CLCN2 associated with several IGE sub-types. There has also been progress in understanding the non-mendelian IGEs. A haplotype in the Malic Enzyme 2 gene, ME2, increases the risk for IGE in the homozygous state. Five missense mutations have been identified in EFHC1 in 6 of 44 families with JME. Rare sequence variants have been identified in CACNA1H in sporadic patients with childhood absence epilepsy in the Chinese Han population. These advances should lead to new approaches to diagnosis and treatment.
 ...
PMID:Genetics of idiopathic generalized epilepsies. 1630 72

Genetic analyses of familial epilepsies over the past decade have identified mutations in several different ion channel genes that result in neonatal or early-onset seizure disorders, including benign familial neonatal convulsions (BFNC), generalized epilepsy with febrile seizures plus (GEFS+), and severe myoclonic epilepsy of infancy (SMEI). These genes encode voltage-gated Na+ channel subunits (SCN1A, SCN2A, SCN1B), voltage-gated K+ channel subunits (KCNQ2, KCNQ3), and a ligand-gated neurotransmitter receptor subunit (GABRG2). While the opportunity to genotype patients for mutations in these genes can have an immediate and significant impact on our ability to diagnose and provide genetic counseling to patients, the ultimate goal is to use this molecular knowledge to develop effective treatments and cures for each disorder. This will necessitate elucidation of the molecular, cellular, and network mechanisms that translate ion channel defects into specific epilepsy phenotypes. The functional analysis of epileptogenic channel mutations in vitro and in vivo has already provided a vast amount of raw biophysical data, but attempts to interpret these data to explain clinical phenotypes so far appear to raise as many questions as they answer. Nevertheless, patterns are beginning to emerge from these early studies that will help define the full scope of the challenges ahead while simultaneously providing the foundation of future efforts to overcome them. Here, I discuss some of the potential mechanisms that have been uncovered recently linking mutant ion channel genes to neonatal epilepsy syndromes and GEFS+.
 ...
PMID:Neonatal epilepsy syndromes and GEFS+: mechanistic considerations. 1635 73

The M-type K+ current [IK(M)] activates in response to membrane depolarization and regulates neuronal excitability. Mutations in two subunits (KCNQ2 and KCNQ3; Kv7.2 and Kv7.3) that underlie the M-channel cause the human seizure disorder benign familial neonatal convulsions (BFNC), presumably by reducing IK(M) function. In mice, the Szt1 mutation, which deletes the genomic DNA encoding the KCNQ2 C terminus and all of CHRNA4 (nicotinic acetylcholine receptor alpha4 subunit) and ARFGAP-1 (GTPase-activating protein that inactivates ADP-ribosylation factor 1), reduces seizure threshold, and alters M-channel pharmacosensitivity. Genomic deletions affecting the C terminus of KCNQ2 have been identified in human families with BFNC, and truncation of the C terminus prevents proper KCNQ2/KCNQ3 channel assembly in Xenopus oocytes. We showed previously that Szt1 mice have a reduced baseline seizure threshold and altered sensitivity to drugs that act at the M-channel. Specifically, the proconvulsant M-channel blocker linopirdine and anticonvulsant enhancer retigabine display increased and decreased potency, respectively, in Szt1 mice. To investigate the effects of the Szt1 mutation on IK(M) function explicitly, perforated-patch electrophysiology was performed in CA1 pyramidal neurons of the hippocampus in brain slices prepared from C57BL/6J-Szt1/+ and control C57BL/6J+/+ mice. Our results show that Szt1 reduces both IK(M) amplitude and current density, inhibits spike frequency adaptation, and alters many aspects of M-channel pharmacology. This is the first evidence that a naturally occurring Kcnq2 mutation diminishes the amplitude and function of the native neuronal IK(M), resulting in significantly increased neuronal excitability. Finally, the changes in single-cell biophysical properties likely underlie the altered seizure threshold and pharmacosensitivity reported previously in Szt1 mice.
 ...
PMID:A spontaneous mutation involving Kcnq2 (Kv7.2) reduces M-current density and spike frequency adaptation in mouse CA1 neurons. 1648 38

The syndrome of benign familial neonatal convulsions (BFNC) is characterized by seizures starting within the first days of life and disappearing within weeks to months. BFNC is caused by loss-of-function mutations in the potassium channels KCNQ2 and KCNQ3 which can well explain the resulting neuronal hyperexcitability. However, it is not understood why seizures predominantly occur in the neonatal period. A potential explanation might be a change in the expression pattern of these channels during development. We therefore performed an immunohistochemical analysis of mouse brain slices at different stages of postnatal development using an antibody recognizing the C-terminus of the KCNQ2 channel. A widespread immunohistochemical staining was observed, particularly in the hippocampus, caudoputamen, globus pallidus, cortex, thalamus, hypothalamus and midbrain. In the adult mouse brain, a predominantly axonal staining pattern was found, most observed in the caudoputamen, the alveus and the mossy fiber pathway of the hippocampus. The hippocampal staining pattern of adult mice was not observed before P8 and gradually developed between P11 and P21. Differences in the distribution of KCNQ2 channels within neurons between the neonatal period and adult stages might contribute to the increased seizure susceptibility in BFNC in humans.
 ...
PMID:Immunohistochemical analysis of KCNQ2 potassium channels in adult and developing mouse brain. 1650 Jun 30

Mutations that reduce the function of KCNQ2 channels cause neuronal hyperexcitability, manifested as epileptic seizures and myokymia. These channels are present in nodes of Ranvier in rat brain and nerve and have been proposed to mediate the slow nodal potassium current I(Ks). We have used immunocytochemistry, electrophysiology and pharmacology to test this hypothesis and to determine the contribution of KCNQ channels to nerve excitability in the rat. When myelinated nerve fibres of the sciatic nerve were examined by immunofluorescence microscopy using antibodies against KCNQ2 and KCNQ3, all nodes showed strong immunoreactivity for KCNQ2. The nodes of about half the small and intermediate sized fibres showed labelling for both KCNQ2 and KCNQ3, but nodes of large fibres were labelled by KCNQ2 antibodies only. In voltage-clamp experiments using large myelinated fibres, the selective KCNQ channel blockers XE991 (IC50 = 2.2 microm) and linopirdine (IC50 = 5.5 microm) completely inhibited I(Ks), as did TEA (IC50 = 0.22 mm). The KCNQ channel opener retigabine (10 microm) shifted the activation curve to more negative membrane potentials by -24 mV, thereby increasing I(Ks). In isotonic KCl 50% of I(Ks) was activated at -62 mV. The activation curve shifted to more positive potentials as [K+]o was reduced, so that the pharmacological and biophysical properties of I(Ks) were consistent with those of heterologously expressed homomeric KCNQ2 channels. The ability of XE991 to selectively block I(Ks) was further exploited to study I(Ks) function in vivo. In anaesthetized rats, the excitability of tail motor axons was indicated by the stimulus current required to elicit a 40% of maximal compound muscle action potential. XE991 (2.5 mg kg(-1) i.p.) eliminated all nerve excitability functions previously attributed to I(Ks): accommodation to 100 ms subthreshold depolarizing currents, the post-depolarization undershoot in excitability, and the late subexcitability after a single impulse or short trains of impulses. Due to reduced spike-frequency adaptation after XE991 treatment, 100 ms suprathreshold current injections generated long trains of action potentials. We conclude that the nodal I(Ks) current is mediated by KCNQ channels, which in large fibres of rat sciatic nerve appear to be KCNQ2 homomers.
 ...
PMID:KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. 1652 53

Retigabine has anticonvulsant properties that appear to be primarily mediated by opening neuronal voltage-gated potassium channels. This action has been shown in neuronal KCNQ2/3 and KCNQ3/5 potassium channels. In addition to this unique action, retigabine also potentiates GABA-evoked currents in cortical neurons at high concentrations. When used as adjunctive therapy in patients with partial seizures, retigabine 600-1200 mg/day (200-400 mg three times daily) was associated with significant linear dose-dependent reductions in monthly seizure frequency compared with placebo in a large 16-week randomised phase II trial. Median monthly seizure frequency decreased from baseline by up to 35% among patients in the retigabine treatment arms compared with 13% in the placebo group. Retigabine 1200 mg/day was also significantly more effective than retigabine 600 mg/day. Responder rates, defined as the proportion of patients with > or = 50% reduction in seizure frequency, were significantly higher among patients in the retigabine 900 and 1200 mg/day groups than in those who received placebo. CNS-related adverse events were the most commonly reported treatment-emergent adverse events associated with retigabine in clinical trials. Across all three retigabine groups in the large phase II trial, somnolence (20.3%), dizziness (14.6%), confusion (12.3%) and speech disorder (11.3%) were the most frequent CNS-related adverse events.
 ...
PMID:Retigabine: in partial seizures. 1680 Jul 18


<< Previous 1 2 3 4 5 6 7 8 Next >>