Dataset Information

Remodelling of human atrial K+ currents but not ion channel expression by chronic ?-blockade.

ABSTRACT: Chronic ?-adrenoceptor antagonist (?-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K(+) currents. The aim of this study was to investigate the effects of chronic ?-blockade on transient outward, sustained and inward rectifier K(+) currents (I(TO), I(KSUS) and I(K1)) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic ?-blockade was associated with a 41% reduction in I(TO) density: 9.3?±?0.8 (30 myocytes, 15 patients) vs 15.7?±?1.1 pA/pF (32, 14), p?

SUBMITTER: Marshall GE

PROVIDER: S-EPMC3307334 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade.

Marshall Gillian E GE Russell Julie A JA Tellez James O JO Jhund Pardeep S PS Currie Susan S Dempster John J Boyett Mark R MR Kane Kathleen A KA Rankin Andrew C AC Workman Antony J AJ

Pflugers Archiv : European journal of physiology 20111208 4

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K(+) currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K(+) currents (I(TO), I(KSUS) and I(K1)) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion curren ...[more]

PMID: 22160437

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Project description:Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel's selectivity filters to reach the channel's central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed "state-of-the-art" steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure-property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.

Dataset Information

Remodelling of human atrial K+ currents but not ion channel expression by chronic ?-blockade.

Publications

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade.

Similar Datasets

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