title: An Extended Structure-Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors.
abstract: Nondioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca2+channels (RyRs) and this activation has been associated with neurotoxicity in exposed animals. RyR-active congeners follow a distinct structure-activity relationship and a quantitative structure-activity relationship (QSAR) predicts that a large number of PCBs likely activate the receptor, which requires validation. Additionally, previous structural based conclusions have been established using receptor ligand binding assays but the impact of varying PCB structures on ion channel gating behavior is not understood. We used [3H]Ryanodine ([3H]Ry) binding to assess the RyR-activity of 14 previously untested PCB congeners evaluating the predictability of the QSAR. Congeners determined to display widely varying potency were then assayed with single channel voltage clamp analysis to assess direct influences on channel gating kinetics. The RyR-activity of individual PCBs assessed in in vitro assays followed the general pattern predicted by the QSAR but binding and lipid bilayer experiments demonstrated higher potency than predicted. Of the 49 congeners tested to date, tetra-ortho PCB 202 was found to be the most potent RyR-active congener increasing channel open probability at 200 pM. Shifting meta-substitutions to the para-position resulted in a > 100-fold reduction in potency as seen with PCB 197. Non-ortho PCB 11 was found to lack activity at the receptor supporting a minimum mono-ortho substitution for PCB RyR activity. These findings expand and support previous SAR assessments; where out of the 49 congeners tested to date 42 activate the receptor demonstrating that the RyR is a sensitive and common target of PCBs.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California; erika.holland@csulb.edu.|Department of Biological Sciences, California State University of Long Beach, Long Beach, California.|Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Holland
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California.|Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing 211198, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa.
authors.forename: Xueshu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California.|The Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.|UC Davis Center for Children's Environmental Health and Disease Prevention, Davis, California.
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008962:Models, Theoretical; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D011869:Radioligand Assay; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D014316:Tritium; D011078:Polychlorinated Biphenyls
keywords: neurotoxicity.; nondioxin-like PCBs; ryanodine receptor; single-channel gating