Structure-activity relationship of selected Meta-and Para-hydroxylated non-dioxin like polychlorinated biphenyls: From single RyR1 channels to muscle dysfunction

Yassaman Niknam, Wei Feng, Gennady Cherednichenko, Yao Dong, Sudhir N. Joshi, Sandhya M. Vyas, Hans Joachim Lehmler, Isaac N Pessah

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Non-dioxin like polychlorinated biphenyls (NDL-PCBs) are legacy environmental contaminants with contemporary unintentional sources. NDL-PCBs interact with ryanodine receptors (RyRs), Ca2+ channels of sarcoplasmic/endoplasmic reticulum (SR/ER) that regulate excitation-contraction coupling (ECC) and Ca2+-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 [3H]ryanodine binding and SR Ca2+ flux analyses. Although 5-OH metabolites have comparable activity to their respective parent in both assays, 4-OH derivatives are unable to trigger Ca2+ release from SR microsomes in the presence of Ca2+-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 (po>.9) by stabilizing the full-open channel state, whereas 4-OH-PCB95 transiently enhances po. Ca2+ imaging of myotubes loaded with Fluo-4 show that acute exposure to PCB95 (5μM) potentiates ECC and caffeine responses and partially depletes SR Ca2+ stores. Exposure to 5-OH-PCB95 (5 μM) increases cytoplasmic Ca2+, leading to rapid ECC failure in 50% of myotubes with the remainder retaining negligible responses. 4-OH-PCB95 neither increases baseline Ca2+ nor causes ECC failure but depresses ECC and caffeine responses by 50%. With longer (3 h) 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)500-513
Number of pages14
JournalToxicological Sciences
Volume136
Issue number2
DOIs
StatePublished - Dec 2013

Keywords

  • Calcium signaling
  • Hydroxylated metabolites
  • Muscle dysfunction
  • Polychlorinated biphenyls
  • Ryanodine receptor

ASJC Scopus subject areas

  • Toxicology

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