An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

Erika B Holland; Wei Feng; Jing Zheng; Yao Dong; Xueshu Li; Hans-Joachim Lehmler; Isaac N Pessah

doi:10.1093/toxsci/kfw189

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An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

Journal article

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Peer reviewed

An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

Erika B Holland, Wei Feng, Jing Zheng, Yao Dong, Xueshu Li, Hans-Joachim Lehmler and Isaac N Pessah

Toxicological sciences, Vol.155(1), pp.170-181

01/2017

DOI: 10.1093/toxsci/kfw189

PMCID: PMC5216651

PMID: 27655348

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Abstract

Nondioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca 2+ 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 [ 3 H]Ryanodine ([ 3 H]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.

single-channel gating

Nondioxin-Like PCBs and Ryanodine Receptors

neurotoxicity

ryanodine receptor

nondioxin-like PCBs

Synthesis Core

UC-Davis collaboration

Details

Title: Subtitle: An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors
Creators: Erika B Holland - Department of Biological Sciences, California State University of Long Beach, Long Beach, California
Wei Feng - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California
Jing Zheng - Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing 211198, China
Yao Dong - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California
Xueshu Li - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa
Isaac N Pessah - UC Davis Center for Children’s Environmental Health and Disease Prevention, Davis, California
Resource Type: Journal article
Publication Details: Toxicological sciences, Vol.155(1), pp.170-181
DOI: 10.1093/toxsci/kfw189
PMID: 27655348
PMCID: PMC5216651
NLM abbreviation: Toxicol Sci
ISSN: 1096-6080
eISSN: 1096-0929
Publisher: Oxford University Press
Language: English
Date published: 01/2017
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
Record Identifier: 9984000920902771

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