Journal article
Structure-Activity Relationship of Selected Meta- and Para-Hydroxylated Non–Dioxin Like Polychlorinated Biphenyls: From Single RyR1 Channels to Muscle Dysfunction
Toxicological sciences, Vol.136(2), pp.500-513
12/2013
DOI: 10.1093/toxsci/kft202
PMCID: PMC3858193
PMID: 24014653
Abstract
Non–dioxin like polychlorinated biphenyls (NDL-PCBs) are legacy environmental contaminants with contemporary unintentional sources. NDL-PCBs interact with ryanodine receptors (RyRs), Ca
2+
channels of sarcoplasmic/endoplasmic reticulum (SR/ER) that regulate excitation-contraction coupling (ECC) and Ca
2+
-dependent cell signaling in muscle. Activities of 4 chiral congeners PCB91, 95, 132, and 149 and their respective 4- and 5-hydroxy (-OH) derivatives toward rabbit skeletal muscle ryanodine receptor (RyR1) are investigated using [
3
H]ryanodine binding and SR Ca
2+
flux analyses. Although 5-OH metabolites have comparable activity to their respective parent in both assays, 4-OH derivatives are unable to trigger Ca
2+
release from SR microsomes in the presence of Ca
2+
-ATPase activity. PCB95 and derivatives are investigated using single channel voltage-clamp and primary murine embryonic muscle cells (myotubes). Like PCB95, 5-OH-PCB95 quickly and persistently increases channel open probability (
p
o
> .9) by stabilizing the full-open channel state, whereas 4-OH-PCB95 transiently enhances
p
o
. Ca
2+
imaging of myotubes loaded with Fluo-4 show that acute exposure to PCB95 (5µM) potentiates ECC and caffeine responses and partially depletes SR Ca
2+
stores. Exposure to 5-OH-PCB95 (5 µM) increases cytoplasmic Ca
2+
, leading to rapid ECC failure in 50% of myotubes with the remainder retaining negligible responses. 4-OH-PCB95 neither increases baseline Ca
2+
nor causes ECC failure but depresses ECC and caffeine responses by 50%. With longer (3h) exposure to 300nM PCB95, 5-OH-PCB95, or 4-OH-PCB95 decreases the number of ECC responsive myotubes by 22%, 81%, and 51% compared with control by depleting SR Ca
2+
and/or uncoupling ECC. NDL-PCBs and their 5-OH and 4-OH metabolites differentially influence RyR1 channel activity and ECC in embryonic skeletal muscle.
Details
- Title: Subtitle
- Structure-Activity Relationship of Selected Meta- and Para-Hydroxylated Non–Dioxin Like Polychlorinated Biphenyls: From Single RyR1 Channels to Muscle Dysfunction
- Creators
- Yassaman Niknam - Department of Molecular Biosciences, School of Veterinary Medicine, University of CaliforniaWei Feng - Department of Molecular Biosciences, School of Veterinary Medicine, University of CaliforniaGennady Cherednichenko - Department of Molecular Biosciences, School of Veterinary Medicine, University of CaliforniaYao Dong - Department of Molecular Biosciences, School of Veterinary Medicine, University of CaliforniaSudhir N Joshi - Department of Occupational and Environmental Health, College of Public Health, University of IowaSandhya M Vyas - Department of Occupational and Environmental Health, College of Public Health, University of IowaHans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of IowaIsaac N Pessah - The Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California at Davis
- Resource Type
- Journal article
- Publication Details
- Toxicological sciences, Vol.136(2), pp.500-513
- DOI
- 10.1093/toxsci/kft202
- PMID
- 24014653
- PMCID
- PMC3858193
- NLM abbreviation
- Toxicol Sci
- ISSN
- 1096-6080
- eISSN
- 1096-0929
- Publisher
- Oxford University Press; US
- Language
- English
- Date published
- 12/2013
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute
- Record Identifier
- 9984000930602771
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