title: Structure-activity relationship of selected meta- and para-hydroxylated non-dioxin like polychlorinated biphenyls: from single RyR1 channels to muscle dysfunction.
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 (5 µM) 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 300 nM 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.
authors.affiliation: * Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616;
authors.forename: Yassaman
authors.initials: Y
authors.lastname: Niknam
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Gennady
authors.initials: G
authors.lastname: Cherednichenko
authors.forename: Yao
authors.initials: Y
authors.lastname: Dong
authors.forename: Sudhir N
authors.initials: SN
authors.lastname: Joshi
authors.forename: Sandhya M
authors.initials: SM
authors.lastname: Vyas
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D011078:Polychlorinated Biphenyls; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: calcium signaling; hydroxylated metabolites.; muscle dysfunction; polychlorinated biphenyls; ryanodine receptor