Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

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Frontispiece: Micro- and Nano-Technologies for Lipid Bilayer-Based Ion-Channel Functional Assays

Chemistry - An Asian Journal ◽

10.1002/asia.201580661 ◽

2015 ◽

Vol 10 (6) ◽

pp. n/a-n/a

Author(s):

Ayumi Hirano-Iwata ◽

Yutaka Ishinari ◽

Hideaki Yamamoto ◽

Michio Niwano

Keyword(s):

Ion Channel ◽

Lipid Bilayer ◽

Functional Assays

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Direct Binding of Phosphatidylglycerol at Specific Sites Modulates Desensitization of a Pentameric Ligand-Gated Ion Channel

10.1101/722512 ◽

2019 ◽

Author(s):

Ailing Tong ◽

John T. Petroff ◽

Fong-Fu Hsu ◽

Philipp A. M. Schmidpeter ◽

Crina M. Nimigean ◽

...

Keyword(s):

Ion Channel ◽

Transmembrane Domain ◽

Native Mass Spectrometry ◽

Coarse Grained ◽

Specific Lipids ◽

Anionic Phospholipid ◽

Anionic Phospholipids ◽

Functional Assays ◽

Direct Binding ◽

Dynamics Simulations

AbstractPentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, the L240A mutant known to decrease ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

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Myrsinane and related diterpenes from Euphorbia falcata with selective potassium ion channel activity

Planta Medica ◽

10.1055/s-0035-1565539 ◽

2015 ◽

Vol 81 (16) ◽

Author(s):

A Vasas ◽

P Orvos ◽

L Tálosi ◽

P Forgo ◽

G Pinke ◽

...

Keyword(s):

Ion Channel ◽

Potassium Ion ◽

Channel Activity ◽

Potassium Ion Channel

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Ion channel alterations and epilepsy in mice and man

Neuropediatrics ◽

10.1055/s-2005-867952 ◽

2005 ◽

Vol 36 (02) ◽

Author(s):

CM Becker ◽

J Brill ◽

K Becker

Keyword(s):

Ion Channel

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Ion Channel Remodelling in Atrial Fibrillation

European Cardiology Review ◽

10.15420/ecr.2011.7.2.97 ◽

2011 ◽

Vol 7 (2) ◽

pp. 97 ◽

Cited By ~ 6

Author(s):

Niels Voigt ◽

Dobromir Dobrev ◽

◽

Keyword(s):

Atrial Fibrillation ◽

Ion Channel ◽

Antiarrhythmic Drugs ◽

Current Knowledge ◽

Bleeding Complications ◽

Large Size ◽

Cardiovascular Morbidity And Mortality ◽

Number Of Patients ◽

Life Threatening ◽

Underlying Mechanisms

Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication. Present drugs used for the therapy of AF (antiarrhythmics and anticoagulants) have major limitations, including incomplete efficacy, risks of life-threatening proarrhythmic events and bleeding complications. Non-pharmacological ablation procedures are efficient and apparently safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. These limitations largely result from limited knowledge about the underlying mechanisms of AF and there is a hope that a better understanding of the molecular basis of AF may lead to the discovery of safer and more effective therapeutic targets. This article reviews the current knowledge about AF-related ion-channel remodelling and discusses how these alterations might affect the efficacy of antiarrhythmic drugs.

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