Overview of Molecular Relationships in the Voltage-Gated Ion Channel Superfamily

Yu, Frank H.; Yarov‐Yarovoy, Vladimir; Gutman, George A.; Catterall, William A.

doi:10.1124/pr.57.4.13

Cited by 443 publications

(368 citation statements)

References 114 publications

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“…37,38 This superfamily encompasses the S4 family in which the pore-forming subunits are built on a motif of six transmembrane segments (S1-S6) the fourth of which (S4) contains a voltage-sensing element. In voltage-gated Na ϩ and Ca 2ϩ channels, four such domains (referred to as I-IV or D1-D4) are expressed as a single polypeptide arranged around a central pore that conducts the ionic current.…”

Section: Voltage-gated Ion 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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Section: Voltage-gated Ion Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…3,52 A few basic principles, however, are necessary to appreciate the effects of mutations on the biophysical properties of the channel.…”

Section: Molecular Biology Of Ea-1mentioning

confidence: 99%

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

et al. 2007

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Summary: Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A, the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.

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“…VGIC complements vary with cell type (3), making cell-specific channels important targets to selectively modulate pathophysiological electrical signals (4). There are over 80 VGIC pore-forming subunits encoded in the human genome (5), and many of these are coexpressed within the same cell (3), making it difficult to dissect specific channel contributions to electrical signaling. In neurons, the precise trafficking of VGIC subtypes to distinct cell regions such as the axon hillock, presynaptic terminals, and distal dendrites allows specific subtypes to control voltage changes in subcellular compartments (6)(7)(8)(9).…”

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confidence: 99%

Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells

Tilley

Eum

Fletcher-Taylor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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111

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Significance Electrically excitable cells, such as neurons, exhibit tremendous variation in their patterns of electrical signals. These variations arise from the collection of ion channels present in any specific cell, but understanding which ion channels are at the root of particular electrical signals remains a significant challenge. Here, we describe novel probes, derived from a tarantula venom peptide, that are able to report the activity of voltage-gated ion channels in living cells. This technology uses state-selective binding to optically monitor the activation of ion channels during cellular electrical signaling. Activity-reporting probes based on these prototypes could potentially identify when endogenous ion channels contribute to electrical signaling, thus facilitating the identification of ion channel targets for therapeutic drug intervention.

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Overview of Molecular Relationships in the Voltage-Gated Ion Channel Superfamily

Cited by 443 publications

References 114 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells

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