scholarly journals The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations

2018 ◽  
Author(s):  
Smiruthi Ramasubramanian ◽  
Yoram Rudy
Keyword(s):  
Ion Channel ◽  
Physiological Function ◽  
Structural Basis ◽  
Computational Techniques ◽  
Step Voltage ◽  
Gating Charge ◽  
Current Activation ◽  
Life Threatening ◽  
Molecular Components ◽  
Sequential Gating

ABSTRACTRelating ion-channel (iCh) structural dynamics to physiological function remains a challenge. Current experimental and computational techniques have limited ability to explore this relationship in atomistic detail over physiological timescales. A framework associating iCh structure to function is necessary for elucidating normal and disease mechanisms. We formulated a modeling schema that overcomes the limitations of current methods through applications of Artificial Intelligence Machine Learning (ML). Using this approach, we studied molecular processes that underlie human IKs voltage mediated gating. IKs malfunction underlies many debilitating and life-threatening diseases. Molecular components of IKs that underlie its electrophysiological function include KCNQ1 (pore forming tetramer) and KCNE1 (auxiliary subunit). Simulations, using the IKs structure-function model, reproduced experimentally recorded saturation of gating charge displacement at positive membrane voltages, two-step voltage sensor (VS) movement shown by fluorescence, iCh gating statistics, and current-voltage (I-V) relationship. New mechanistic insights include - (1) pore energy profile determines iCh subconductance (SC), (2) entire protein structure, not limited to the pore, contributes to pore energy and channel SC, (3) interactions with KCNE1 result in two distinct VS movements, causing gating charge saturation at positive membrane voltages and current activation delay, and (4) flexible coupling between VS and pore permits pore opening at lower VS positions, resulting in sequential gating. The new modeling approach is applicable to atomistic scale studies of other proteins on timescales of physiological function.

Ion Channel Remodelling in Atrial Fibrillation

2011 ◽  
Vol 7 (2) ◽  
pp. 97 ◽  
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.

scholarly journals Cryo-EM structures of a lipid-sensitive pentameric ligand-gated ion channel embedded in a phosphatidylcholine-only bilayer

2020 ◽  
Vol 117 (3) ◽  
pp. 1788-1798 ◽  
Author(s):  
Pramod Kumar ◽  
Yuhang Wang ◽  
Zhening Zhang ◽  
Zhiyu Zhao ◽  
Gisela D. Cymes ◽  
...  
Keyword(s):  
Ion Channel ◽  
Binding Sites ◽  
Electric Organ ◽  
Structural Models ◽  
Erwinia Chrysanthemi ◽  
Structural Basis ◽  
Agonist Binding ◽  
Nicotinic Acetylcholine ◽  
Bacterial Homolog ◽  
Straightforward Interpretation

The lipid dependence of the nicotinic acetylcholine receptor from the Torpedo electric organ has long been recognized, and one of the most consistent experimental observations is that, when reconstituted in membranes formed by zwitterionic phospholipids alone, exposure to agonist fails to elicit ion-flux activity. More recently, it has been suggested that the bacterial homolog ELIC (Erwinia chrysanthemi ligand-gated ion channel) has a similar lipid sensitivity. As a first step toward the elucidation of the structural basis of this phenomenon, we solved the structures of ELIC embedded in palmitoyl-oleoyl-phosphatidylcholine- (POPC-) only nanodiscs in both the unliganded (4.1-Å resolution) and agonist-bound (3.3 Å) states using single-particle cryoelectron microscopy. Comparison of the two structural models revealed that the largest differences occur at the level of loop C—at the agonist-binding sites—and the loops at the interface between the extracellular and transmembrane domains (ECD and TMD, respectively). On the other hand, the transmembrane pore is occluded in a remarkably similar manner in both structures. A straightforward interpretation of these findings is that POPC-only membranes frustrate the ECD–TMD coupling in such a way that the “conformational wave” of liganded-receptor gating takes place in the ECD and the interfacial M2–M3 linker but fails to penetrate the membrane and propagate into the TMD. Furthermore, analysis of the structural models and molecular simulations suggested that the higher affinity for agonists characteristic of the open- and desensitized-channel conformations results, at least in part, from the tighter confinement of the ligand to its binding site; this limits the ligand’s fluctuations, and thus delays its escape into bulk solvent.

scholarly journals Gating charge movement precedes ionic current activation in hERG channels

Channels ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. 84-89 ◽  
Author(s):  
Samuel J Goodchild ◽  
David Fedida
Keyword(s):  
Ionic Current ◽  
Charge Movement ◽  
Gating Charge ◽  
Current Activation ◽  
Herg Channels

scholarly journals Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

2017 ◽  
Vol 112 (3) ◽  
pp. 321a
Author(s):  
Qiang Chen ◽  
Marta M. Wells ◽  
Tommy S. Tillman ◽  
Monica N. Kinde ◽  
Aina Cohen ◽  
...  
Keyword(s):  
Ion Channel ◽  
Structural Basis

scholarly journals Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Ludovic Sauguet ◽  
Rebecca J. Howard ◽  
Laurie Malherbe ◽  
Ui S. Lee ◽  
Pierre-Jean Corringer ◽  
...  
Keyword(s):  
Ion Channel ◽  
Structural Basis

Structural basis of ion channel permeation and selectivity

1994 ◽  
Vol 4 (3) ◽  
pp. 313-323 ◽  
Author(s):  
William A. Sather ◽  
Jian Yand ◽  
Richard W. Tsien
Keyword(s):  
Ion Channel ◽  
Structural Basis
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