Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

Du, Wei; Bautista, Jocelyn F.; Yang, Huanghe; Dı́ez-Sampedro, Ana; You, Sun Kyoung; Wang, Lejin; Kotagal, Prakash; Lüders, Hans; Shi, Jingyi; Cui, Jianmin; Richerson, George B.; Wang, Qing Kenneth

doi:10.1038/ng1585

Cited by 546 publications

(652 citation statements)

References 28 publications

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“…Recent genetic studies indicate that a gain-of-function BK channel mutation (increased open probability) is responsible for generalized epilepsy in humans (Du et al, 2005). In this study, several mechanisms were proposed to explain the paradoxical increase in excitability at thalamo-cortical circuits by a mutated BK channels exhibiting increased open-channel probability.…”

Section: Discussionmentioning

confidence: 88%

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Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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Section: Discussionmentioning

confidence: 88%

“…Recent genetic studies have implicated enhanced BK channel function in the pathogenesis of genetic epilepsy (Du et al, 2005). In another study, the gene encoding the β3 subunit (Kcnmb3) has been associated with idiopathic epilepsy (Lorenz et al, 2006) and increased neuronal excitability (Hu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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“…The authors also found a missense variation that alters a conserved domain of the channel in one patient with ASD (Laumonnier et al., 2006; Table 2). Furthermore, a variation in the α 1 subunit of BK Ca channel ( KCNMA1) has been implicated in generalized epilepsy and paroxysmal dyskinesia (Du et al., 2005). A novel missense variation (c.595A.T) in KCNB1 gene that encodes K V 2.1 voltage‐gated potassium channel was detected in a patient with ASD associated with intellectual disability and epilepsy.…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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“…It was a surprise, therefore, when mutations in the KCNMA1 gene, which encodes the ␣ subunit of K Ca 1.1, were associated with a syndrome of generalized epilepsy and paroxysmal dyskinesia. 123 In contrast to typical K ϩ channelopathies associated with epilepsy, in which there is a loss of function, mutant BK channels exhibited a gain of function. Indeed, the channels conducted markedly greater macroscopic current due to an increase in the single-channel open probability and an enhancement in their Ca 2ϩ sensitivity.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

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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Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder

Cited by 546 publications

References 28 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Autism throughout genetics: Perusal of the implication of ion channels

Molecular Targets for Antiepileptic Drug Development

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