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.
Highlights
Bisphenol A (BPA) is used abundantly in the manufacture of polycarbonate plastics and epoxy resins
BPA Blocks hNav1.5 Currents To investigate the effects of BPA on cardiac sodium channel function, we transiently expressed hNav1.5 in HEK cells and performed whole-cell patch clamp experiments (Fig. 1)
The predominant block of BPA at this holding potential may result from a higher binding affinity of the compound to the inactivated state, which is the case for local anesthetic (LA), where dissociation constants for inactivated channels is much lower than for resting channels (Ki,Kr)
Summary
Bisphenol A (BPA) is used abundantly in the manufacture of polycarbonate plastics and epoxy resins. Millions of tons of BPA are produced annually and it is detectable in the urine and blood of a large section of the population [1,2,3]. Given the short half-life (,6 hours) of BPA in the body [4], its frequent detection indicates that there is pervasive environmental exposure to the compound. Two studies have shown a correlation between urine concentration of BPA and heart disease in human populations [7,8]. While BPA has been characterized as an endocrine disruptor, displaying weak agonistic effects at estrogenic receptors [9,10], the broad spectrum of suspected BPA-associated diseases, including disorders of the heart, suggests additional molecular targets may exist
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