title: Bisphenol A binds to the local anesthetic receptor site to block the human cardiac sodium channel.
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 K(d) 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.
authors: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Bavaria, Germany.
authors: Andrias O
authors: AO
authors: O'Reilly
authors: Esther
authors: E
authors: Eberhardt
authors: Christian
authors: C
authors: Weidner
authors: Christian
authors: C
authors: Alzheimer
authors: B A
authors: BA
authors: Wallace
authors: Angelika
authors: A
authors: Lampert
mesh_terms: D000595:Amino Acid Sequence; D000779:Anesthetics, Local / Q000378:metabolism*; D001559:Benzhydryl Compounds / Q000378:metabolism* / Q000633:toxicity*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008801:Mexiletine / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism* / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D026941:Sodium Channel Blockers / Q000378:metabolism / Q000633:toxicity; D000098826:Bisphenol A Compounds
chemical_list: D000779:Anesthetics, Local; D001559:Benzhydryl Compounds; D004785:Environmental Pollutants; D008024:Ligands; D008801:Mexiletine; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010636:Phenols; D026941:Sodium Channel Blockers; C568320:SCN5A protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds