Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes

Chioza, Barry A.; Osei-Lah, Abena; Wilkie, Hazel; Nashef, Lina; McCormick, David; Asherson, Philip; Makoff, Andrew

doi:10.1016/s0920-1211(02)00195-x

Cited by 34 publications

(19 citation statements)

References 31 publications

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“…For example, an association study linked a polymorphism in KCNJ3 with absence seizures. 126 KCNJ3 encodes K ir 3.1, a channel that induces membrane hyperpolarization in response to activation of G-protein linked receptors. 126 Weaver mice show severe ataxia with loss of cerebellar granule cells and sometimes generalized convulsions.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

“…126 KCNJ3 encodes K ir 3.1, a channel that induces membrane hyperpolarization in response to activation of G-protein linked receptors. 126 Weaver mice show severe ataxia with loss of cerebellar granule cells and sometimes generalized convulsions. They have a mutation in Kcnj6 causing the pore-forming domain of the G-protein activated channel Girk2 to lose ion selectivity.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

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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 Potassium Channelsmentioning

confidence: 99%

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…This perspective, embodied in the terms “channelopathy” and “channelepsy” (Hoffman, 1995; Ptacek, 1997; De Lanerolle et al, 2004; Kullmann and Waxman, 2010; D'adamo et al, 2013), is fueled by the increasing number of ion channel mutations discovered in epilepsy patients (Biervert et al, 1998; Charlier et al, 1998; Singh et al, 1998, 2008; Zuberi et al, 1999; Heilstedt et al, 2001; Chioza et al, 2002; Schulte et al, 2006; Cavalleri et al, 2007; Tomlinson et al, 2010; Lachance-Touchette et al, 2011; Weckhuysen et al, 2013), and the seizure phenotypes of corresponding engineered channel mutants (Signorini et al, 1997; Schroeder et al, 1998; Smart et al, 1998; Spigelman et al, 2002; Ludwig et al, 2003; Peters et al, 2005; Huang et al, 2009; Ishii et al, 2009; Riazanski et al, 2011; Hedrich et al, 2014). In contrast to genetic channelopathies, an “acquired channelopathy” is declared when ion channel abnormalities develop independently of the genetic background (Waxman, 2001; Bernard et al, 2004; Poolos and Johnston, 2012).…”

Section: Introductionmentioning

confidence: 99%

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

Wolfart

Laker

2015

Front. Physiol.

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Neurons continuously adapt the expression and functionality of their ion channels. For example, exposed to chronic excitotoxicity, neurons homeostatically downscale their intrinsic excitability. In contrast, the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy. We review cell type-specific channel alterations under different epileptic conditions and discuss the potential of channels that undergo homeostatic adaptations, as targets for antiepileptic drugs (AEDs). Most of the relevant studies have been performed on temporal lobe epilepsy (TLE), a widespread AED-refractory, focal epilepsy. The TLE patients, who undergo epilepsy surgery, frequently display hippocampal sclerosis (HS), which is associated with degeneration of cornu ammonis subfield 1 pyramidal cells (CA1 PCs). Although the resected human tissue offers insights, controlled data largely stem from animal models simulating different aspects of TLE and other epilepsies. Most of the cell type-specific information is available for CA1 PCs and dentate gyrus granule cells (DG GCs). Between these two cell types, a dichotomy can be observed: while DG GCs acquire properties decreasing the intrinsic excitability (in TLE models and patients with HS), CA1 PCs develop channel characteristics increasing intrinsic excitability (in TLE models without HS only). However, thorough examination of data on these and other cell types reveals the coexistence of protective and permissive intrinsic plasticity within neurons. These mechanisms appear differentially regulated, depending on the cell type and seizure condition. Interestingly, the same channel molecules that are upregulated in DG GCs during HS-related TLE, appear as promising targets for future AEDs and gene therapies. Hence, GCs provide an example of homeostatic ion channel adaptation which can serve as a primer when designing novel anti-epileptic strategies.

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“…GIRK loss-of-function can lead to excessive neuronal excitation, such as in epilepsy (D’Adamo et al, 2013), whereas gain-of-function can substantially reduce neuronal activity, such as when GIRK2 is triplicated in a mouse model of Down syndrome (Best et al, 2007). In humans, alterations in expression levels in KCNJ3 gene have been linked to schizophrenia (Yamada et al, 2011, 2012), epilepsy (Chioza et al, 2002; Lucarini et al, 2007), developmental delays and language impairment (Newbury et al, 2009), and mental retardation in children (Poot et al, 2010). …”

mentioning

confidence: 99%

Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex

et al. 2015

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Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with 14C-2-deoxyglucose. Results showed decreased activation in PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity.

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Suggestive evidence for association of two potassium channel genes with different idiopathic generalised epilepsy syndromes

Cited by 34 publications

References 31 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex

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