Bisphenol A Binds to the Local Anesthetic Receptor Site to Block the Human Cardiac Sodium Channel
Figure 3
BPA and mexiletine share an overlapping binding site.
A: Representative current traces of the mutant channel F1760A evoked by stepping the membrane to the indicated potentials. B: Activation and steady-state fast inactivation of WT hNav1.5 (filled squares, n = 10 and 44, respectively) and the mutant F1760A (open squares, n = 14 and 61, respectively). C: Tonic block of WT hNav1.5 (filled symbols) and the mutant F1760A (open symbols) by BPA (circles) and mexiletine (triangles) at a holding potential of −120 mV, tested every 5 s, n = 3−15 (for protocol see Fig. 1A). Straight lines represent results of a Hill fit, with the following Kds: hNav1.5 BPA: 74.0±7.6 µM; F1760A BPA: 104.1±6.7 µM; hNav1.5 mexiletine: 595.9±41.8 µM; F1750A mexiletine: 1142.5±94.0 µM. The mutation significantly reduced the blocking effects of mexiletine and BPA on hNav1.5. The posthoc test revealed a significant difference for all tested concentrations of BPA and for the highest two concentrations of mexiletine. D: Repetitive pulsing of F1760A expressing HEK cells induces almost no use-dependent current decline (open symbols), which can be enhanced to a limited extent by mexiletine (150 µM, open triangles) or BPA (30µM, open circles). In this Figure data for WT hNav1.5 are the same as in Fig. 1B and are included for comparison (filled symbols). Squares represent use dependencies of the channel without drug application. Asterisks indicate significant differences compared to the untreated channel (WT, F1760A) for each frequency, respectively.