title: Molecular mechanisms underlying the rapid arrhythmogenic action of bisphenol A in female rat hearts.
abstract: Previously we showed that bisphenol A (BPA), an environmental estrogenic endocrine disruptor, rapidly altered Ca(2+) handling and promoted arrhythmias in female rat hearts. The underlying molecular mechanism was not known. Here we examined the cardiac-specific signaling mechanism mediating the rapid impact of low-dose BPA in female rat ventricular myocytes. We showed that protein kinase A (PKA) and Ca(2+)/CaM-dependent protein kinase II (CAMKII) signaling pathways are the two major pathways activated by BPA. Exposure to 1 nM BPA rapidly increased production of cAMP and rapidly but transiently increased the phosphorylation of the ryanodine receptors by PKA but not by CAMKII. BPA also rapidly increased the phosphorylation of phospholamban (PLN), a key regulator protein of sarcoplasmic reticulum Ca(2+) reuptake, by CAMKII but not PKA. The increase in CAMKII phosphorylation of PLN was mediated by phospholipase C and inositol trisphosphate receptor-mediated Ca(2+) release, likely from the endoplasmic reticulum Ca(2+) storage. These two pathways are likely localized, impacting only their respective target proteins. The rapid impacts of BPA on ryanodine receptors and PLN phosphorylation were mediated by estrogen receptor-β but not estrogen receptor-α. BPA's rapid signaling in cardiac myocytes did not involve activation of ERK1/2. Functional analysis showed that PKA but not CAMKII activation contributed to BPA-induced sarcoplasmic reticulum Ca(2+) leak, and both PKA and CAMKII were necessary contributors to the stimulatory effect of BPA on arrhythmogenesis. These results provide mechanistic insight into BPA's rapid proarrhythmic actions in female cardiac myocytes and contribute to the assessment of the consequence and potential cardiac toxicity of BPA exposure.
authors.affiliation: PhD, Department of Pharmacology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575. wanghs@uc.edu.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Gao
authors.forename: Qian
authors.initials: Q
authors.lastname: Liang
authors.forename: Yamei
authors.initials: Y
authors.lastname: Chen
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002118:Calcium; D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds