Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies

Niemeyer, Marı́a Isabel; Yusef, Yamil R.; Cornejo, Isabel; Flores, Carlos A.; Sepúlveda, Francisco V.; Cid, L. Pablo

doi:10.1152/physiolgenomics.00070.2004

Cited by 81 publications

(80 citation statements)

References 47 publications

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“…173 Functional studies in transfected cells suggest that the mutations cause a loss of function. 174 At present, there is no definitive evidence that these mutations are responsible for the epilepsy syndromes; searches for ClC-2 mutations in other cohorts with epilepsy revealed sequence changes that were probably only polymorphisms. In any case, it has been proposed that the epilepsy-associated ClC-2 mutations may lead to alterations in the Cl Ϫ gradient in neurons such that GABA A -mediated inhibition is impaired or may even become excitatory.…”

Section: Voltage-gated Chloride Channelsmentioning

confidence: 96%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Voltage-gated Chloride Channelsmentioning

confidence: 96%

Molecular Targets for Antiepileptic Drug Development

2007

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“…ClC-1 CBS domains bind ATP, ADP, and AMP with similar apparent affinities, inhibiting the channel by shifting the voltage dependence of the common gate to more positive potentials (6, 7, 9 -11). Nucleotide binding to CBS domains also regulates the function of ClC-2 chloride channels (8,12), the plant ClC NO 3 Ϫ /H ϩ antiporter, AtClCa (13), and the Cl Ϫ /H ϩ antiporter ClC-5 (14 -16). In contrast, crystal structures of carboxyl-terminal fragments of ClC-0, a channel closely related to ClC-1, and ClC-Ka channels do not show ATP binding (17,18).…”

mentioning

confidence: 99%

Intracellular β-Nicotinamide Adenine Dinucleotide Inhibits the Skeletal Muscle ClC-1 Chloride Channel

Bennetts

Chen

et al. 2012

Journal of Biological Chemistry

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Background: Weakly voltage-dependent ClC-1 chloride channels regulate skeletal muscle excitability. Results: Intracellular NAD(H) altered the voltage dependence of ClC-1 gating, and specific mutations attenuated this effect. Conclusion: NAD(H) directly inhibits ClC-1 chloride channels by binding to intracellular domains. Significance: ClC-1 inhibition by NAD(H) may play an important role in muscle fatigue and the pathophysiology of myotonia congenita.

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“…Our results showed that, in contrast to the claims in the retracted paper, these altered proteins did not reach the plasma membrane and did not exert any dominant negative effect on the function of normal ClC-2 (ref. 3). Also, in regard to the 2776_2788del11 mutation, using a minigene approach, we could find no difference in the proportion of exon-skipped to normally spliced mRNA as a consequence of the mutation and, on this basis, predicted no alteration in ClC-2-channel expression in affected individuals.…”

mentioning

confidence: 66%

“…A third mutation, G8794A, produces an amino acid replacement (G715E) purportedly associated with a gain of function 1 , allowing the channel to be conductive at reduced intracellular Cl -concentration. We could not reproduce this result of the retracted paper either 3 . The contrast between our results and those in the retracted paper was reflected in the first paragraph of our Discussion section, which reads: "Our results are in marked contrast to those reported previously by Haug et al and suggest that the pathophysiological mechanisms proposed by these authors to account for the phenotype need to be revised" 3 .…”

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confidence: 89%