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Bisphenol A Binds to the Local Anesthetic Receptor Site to Block the Human Cardiac Sodium Channel

O'Reilly, AO, Eberhardt, E, Weidner, C, Alzheimer, C, Wallace, BA and Lampert, A (2012) Bisphenol A Binds to the Local Anesthetic Receptor Site to Block the Human Cardiac Sodium Channel. PLoS One, 7 (7). ISSN 1932-6203

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Abstract

Bisphenol A (BPA) has attracted considerable public attention as it leaches from plastic used in food containers, is detectable in human fluids and recent epidemiologic studies link BPA exposure with diseases including cardiovascular disorders. As heart-toxicity may derive from modified cardiac electrophysiology, we investigated the interaction between BPA and hNav1.5, the predominant voltage-gated sodium channel subtype expressed in the human heart. Electrophysiology studies of heterologously-expressed hNav1.5 determined that BPA blocks the channel with a Kd of 25.4±1.3 µM. By comparing the effects of BPA and the local anesthetic mexiletine on wild type hNav1.5 and the F1760A mutant, we demonstrate that both compounds share an overlapping binding site. With a key binding determinant thus identified, an homology model of hNav1.5 was generated based on the recently-reported crystal structure of the bacterial voltage-gated sodium channel NavAb. Docking predictions position both ligands in a cavity delimited by F1760 and contiguous with the DIII–IV pore fenestration. Steered molecular dynamics simulations used to assess routes of ligand ingress indicate that the DIII–IV pore fenestration is a viable access pathway. Therefore BPA block of the human heart sodium channel involves the local anesthetic receptor and both BPA and mexiletine may enter the closed-state pore via membrane-located side fenestrations.

Item Type: Article
Uncontrolled Keywords: MD Multidisciplinary
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Natural Sciences and Psychology
Publisher: Public Library of Science
Related URLs:
Date Deposited: 26 Sep 2018 09:52
Last Modified: 26 Sep 2018 09:59
DOI or Identification number: 10.1371/journal.pone.0041667
URI: http://researchonline.ljmu.ac.uk/id/eprint/9328

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