Abstract

Bisphenol A (BPA), a high volume production chemical compound attracts growing attention as health relevant xenobiotic in humans. It can directly bind to hormone receptors, enzymes and ion channels to become biologically active. In this study we show that BPA acts as a potent blocker of voltage-activated Ca²⁺channels. We determined the mechanisms of block and the structural elements of BPA essential for its action. Macroscopic Ba²⁺/ Ca²⁺currents through native L-, N-, P/Q-, T-type Ca²⁺channels in rat endocrine GH₃ cells, mouse DRG neurons or cardiac myocytes and recombinant human R-type Ca²⁺channels expressed in HEK293 cells were rapidly and reversibly inhibited by BPA with similar potency (EC₅₀ values: 26 to 35 μM). Pharmacological and biophysical analysis of R-type Ca²⁺ channels revealed that BPA interacts with the extracellular part of the channel protein. Its action does not require intracellular signaling pathways, is neither voltage- nor use-dependent and does not affect channel gating. This indicates that BPA interacts with the channel in its resting state by directly binding to an external site outside the pore forming region. Structure-effect analyses of various phenolic and bisphenolic compounds revealed that (i) a double-alkylated (R-C(CH₃)₂-R, R-C(CH₃)(CH₂CH₃)-R), or double-trifluoromethylated sp³ hybridized carbon atom between the two aromatic rings and (ii) the two aromatic moieties in angulated orientation are optimal for BPA's effectiveness. Since BPA highly pollutes the environment and is incorporated into the human organism our data may provide a basis for future studies relevant for human health and development.