Prediction by Modeling That Epilepsy May Be Caused by Very Small Functional Changes in Ion Channels

Thomas, Evan A.; Reid, Christopher A.; Berkovic, Samuel F.; Petrou, Steven

doi:10.1001/archneurol.2009.219

Cited by 45 publications

(38 citation statements)

References 29 publications

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“…2c). Previous computer simulations suggest that quantitatively similar small alterations (-1 to -5 mV) in the resting membrane potential of neurons (Tigerholm et al 2012) and in the voltage dependence of ion channels (Thomas et al 2009;Tigerholm et al 2012) are effective means to reduce neuronal excitability and prevent epileptic activity. These computer simulations in combination with our experimental findings in DRG neurons and on isolated M-channels suggest that PUFA-induced augmentation of the M-current contributes to the anti-excitable effect of PUFAs.…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

et al. 2016

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Methods: Effects of fatty acids and fatty-acid analogues on mouse dorsal root ganglion neurons and on the human K V 7.2/3 channel expressed in Xenopus laevis oocytes were studied using electrophysiology. Conclusions: These findings suggest that circulating polyunsaturated fatty acids, with a minimum requirement of multiple double bonds and a charged carboxyl group, dampen excitability by opening neuronal M-channels. Collectively, our data bring light to the molecular targets of polyunsaturated fatty acids and thus a possible mechanism by which polyunsaturated fatty acids reduce neuronal excitability. Results

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Section: Discussionmentioning

confidence: 99%

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

et al. 2016

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“…To simplify the presentation of our data, which determined the effects of co-transfecting different masses of ␣1(AD) subunit cDNA on wild type GABA A R expression, we fit the expression levels to the sigmoidal concentration-response equation as follows: Y ϭ 100%/(1 ϩ (X/IC 50 ) Hill slope ), where Y is the expression level of the GABA A R subunit normalized to that obtained in the absence of the ␣1(AD) subunit, and X is the mass of ␣1(AD) subunit cDNA. We must emphasize that although we connected our data points with the fit concentration dependence equation, we are not asserting that the ␣1(AD) subunit necessarily acted by binding competitively with wild type GABA A Rs.…”

Section: Methodsmentioning

confidence: 99%

“…We must emphasize that although we connected our data points with the fit concentration dependence equation, we are not asserting that the ␣1(AD) subunit necessarily acted by binding competitively with wild type GABA A Rs. Therefore, we made statistical comparisons between the mean expression levels instead of the fit IC 50 and Hill slope values.…”

Section: Methodsmentioning

confidence: 99%

“…These findings suggest that a specific threshold of functional GABA A Rs is required to prevent an organism from experiencing a seizure. Moreover, recent computational models of neural networks predicted that very small changes in ion channel function can produce seizure-like activities (50).…”

Section: ␣1(ad) Subunit Reduced ␣3 Subunit Expression To a Greater Exmentioning

confidence: 99%

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GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors

Ding

Feng

Macdonald

et al. 2010

Journal of Biological Chemistry

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A GABA A receptor (GABA A R) ␣1 subunit mutation, A322D (AD), causes an autosomal dominant form of juvenile myoclonic epilepsy (ADJME). Previous studies demonstrated that the mutation caused ␣1(AD) subunit misfolding and rapid degradation, reducing its total and surface expression substantially. Here, we determined the effects of the residual ␣1(AD) subunit expression on wild type GABA A R expression to determine whether the AD mutation conferred a dominant negative effect. We found that although the ␣1(AD) subunit did not substitute for wild type ␣1 subunits on the cell surface, it reduced the surface expression of ␣1␤2␥2 and ␣3␤2␥2 receptors by associating with the wild type subunits within the endoplasmic reticulum and preventing them from trafficking to the cell surface. The ␣1(AD) subunit reduced surface expression of ␣3␤2␥2 receptors by a greater amount than ␣1␤2␥2 receptors, thus altering cell surface GABA A R composition. When transfected into cultured cortical neurons, the ␣1(AD) subunit altered the time course of miniature inhibitory postsynaptic current kinetics and reduced miniature inhibitory postsynaptic current amplitudes. These findings demonstrated that, in addition to causing a heterozygous loss of function of ␣1(AD) subunits, this epilepsy mutation also elicited a modest dominant negative effect that likely shapes the epilepsy phenotype. GABA A Rs2 are ligand-gated ion channels that provide the major source of inhibitory control to the mammalian central nervous system. Each GABA A R is a pentamer whose five subunits arise from seven subunit families that contain multiple subtype isoforms. Neurons preferentially express GABA A Rs composed of distinct combinations of subunit isoforms in different brain regions at well defined times in development (1-3).At maturity, the most prevalent GABA A R throughout the brain consists of two ␣1 subunits, two ␤2 subunits, and one ␥2 subunit in a ␤2-␣1-␤2-␣1-␥2 assembly (4 -6). To date, 13 autosomal dominant mutations in GABA A R subunit genes have been associated with different epilepsy syndromes (7).The missense AD mutation in the GABA A R ␣1 subunit gene (GABRA1) causes ADJME (8), a monogenic form of a common epilepsy syndrome that begins at a distinct developmental time point (adolescence) and confers myoclonic, generalized tonicclonic, and absence seizures as well as neuropsychiatric comorbidities (9). We demonstrated previously that the AD mutation, which substitutes a negatively charged aspartate for a neutral alanine within the M3 transmembrane domain, causes the ␣1(AD) subunit to misfold with altered topology (10). Cells rapidly degrade the misfolded ␣1(AD) subunit through both proteasome-and lysosome-mediated processes (10, 11). Therefore, the ␣1(AD) subunit is expressed at substantially lower levels than the wild type ␣1 subunit. GABA A Rs that do incorporate the residual, nondegraded ␣1(AD) subunits exhibit substantially altered electrophysiological properties (8,12,13). Therefore, a major consequence of heterozygous expression of the AD mutation i...

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“…In this review, we will focus on the relatively recent data showing that cell surface levels of voltage-gated ion channels can be regulated by ubiquitin ligase mediated trafficking pathways. Given that abnormal activity or regulation of voltage-gated ion channels is thought to contribute substantially to the pathology of various neurological diseases such as epilepsy and neuropathic pain, 4,5 this may represent a new paradigm to define changes in voltage-gated ion channel function in disease.…”

Section: Regulation Of Voltage-gated Ion Channels In Excitable Cells mentioning

confidence: 99%

Regulation of voltage-gated ion channels in excitable cells by the ubiquitin ligases Nedd4 and Nedd4-2

Bongiorno¹,

Schuetz²,

Poronnik³

et al. 2011

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Prediction by Modeling That Epilepsy May Be Caused by Very Small Functional Changes in Ion Channels

Cited by 45 publications

References 29 publications

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

Polyunsaturated fatty acids are potent openers of human M‐channels expressed in Xenopus laevis oocytes

GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors

Regulation of voltage-gated ion channels in excitable cells by the ubiquitin ligases Nedd4 and Nedd4-2

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