Physiologic Principles Underlying Ion Channelopathies

Cannon, Stephen C.

doi:10.1016/j.nurt.2007.01.015

Cited by 45 publications

(25 citation statements)

References 23 publications

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“…9 This subunit consists of four repeated domains (I-IV) each of which contains six transmembrane regions (S1-S6) comprising a voltage sensor S4 and a pore loop between S5 and S6 17 (compare Cannon 18 and FIG. 1).…”

Section: Familial Hemiplegic Migraine Type 1 (Fhm1)mentioning

confidence: 99%

Familial Hemiplegic Migraine

2007

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Summary: Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

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Section: Familial Hemiplegic Migraine Type 1 (Fhm1)mentioning

confidence: 99%

Familial Hemiplegic Migraine

2007

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“…Ion channel modulators are attracting interests these years due to their pharmacological values which can treat various diseases such as hypertension, long QT syndrome, diabetes, epilepsy, schizophrenia, depression and pain [6], [7], [15]. Our novel method, the combination of the bacterial spheroplast and the automated patch clamp system, will be able to evaluate the interaction of these membrane proteins and drug candidates with great details without annoying manipulation.…”

Section: Discussionmentioning

confidence: 99%

The application of the Escherichia coli giant spheroplast for drug screening with automated planar patch clamp system

Kikuchi

Sugiura

Nishizawa-Harada

et al. 2015

Biotechnology Reports

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HighlightsHuman Kv2.1 was expressed in the inner membrane of E. coli using prokaryotic codon.Bacterial spheroplasts large enough for the automated patch clamp were prepared by microfluidic chips.Kv2.1 current was recorded from the giant spheroplast by the automated patch clamp.E. coli spheroplasts were used for dose–response assay of potassium channel inhibitors.Our system will become the simple and sensitive drug assay method anyone can use.

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“…These ion channels control muscle contraction, hormones, release of neurotransmitters, and significant biological functions 59. These are located in the lipid bilayer membrane and help during the movement of ions across the hydrophobic barrier that separates the cytoplasm from intracellular and extracellular organelles 60. The function of KCNK18 is to cure the outward potassium channels and produces activated outward current rectifier K + .…”

Section: Introductionmentioning

confidence: 99%

Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18

Sehgal¹,

Hassan²,

Rashid³

2014

DDDT

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Migraine, a complex debilitating neurological disorder is strongly associated with potassium channel subfamily K member 18 (KCNK18). Research has emphasized that high levels of KCNK18 may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like migraine. In the present study, a hybrid approach of molecular docking and virtual screening were followed by pharmacophore identification and structure modeling. Screening was performed using a two-dimensional similarity search against recommended migraine drugs, keeping in view the physicochemical properties of drugs. LigandScout tool was used for exploring pharmacophore properties and designing novel molecules. Here, we report the screening of four novel compounds that have showed maximum binding affinity against KCNK18, obtained through the ZINC database, and Drug and Drug-Like libraries. Docking studies revealed that Asp-46, Ile-324, Ile-44, Gly-118, Leu-338, Val-113, and Phe-41 are critical residues for receptor–ligand interaction. A virtual screening approach coupled with docking energies and druglikeness rules illustrated that ergotamine and PB-414901692 are potential inhibitor compounds for targeting KCNK18. We propose that selected compounds may be more potent than the previously listed drug analogs based on the binding energy values. Further analysis of these inhibitors through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful for designing novel therapeutic targets to cure migraine.

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Physiologic Principles Underlying Ion Channelopathies

Cited by 45 publications

References 23 publications

Familial Hemiplegic Migraine

Familial Hemiplegic Migraine

The application of the Escherichia coli giant spheroplast for drug screening with automated planar patch clamp system

Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18

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