Non-Dioxin-Like Polychlorinated Biphenyls Inhibit G-Protein Coupled Receptor-Mediated Ca2+ Signaling by Blocking Store-Operated Ca2+ Entry

PLoS One. 2016 Mar 10;11(3):e0150921. doi: 10.1371/journal.pone.0150921. eCollection 2016.

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitous pollutants which accumulate in the food chain. Recently, several molecular mechanisms by which non-dioxin-like (NDL) PCBs mediate neurodevelopmental and neurobehavioral toxicity have been elucidated. However, although the G-protein coupled receptor (GPCR) is a significant target for neurobehavioral disturbance, our understanding of the effects of PCBs on GPCR signaling remains unclear. In this study, we investigated the effects of NDL-PCBs on GPCR-mediated Ca2+ signaling in PC12 cells. We found that ortho-substituted 2,2',6-trichlorinated biphenyl (PCB19) caused a rapid decline in the Ca2+ signaling of bradykinin, a typical Gq- and phospholipase Cβ-coupled GPCR, without any effect on its inositol 1,4,5-trisphosphate production. PCB19 reduced thapsigargin-induced sustained cytosolic Ca2+ levels, suggesting that PCB19 inhibits SOCE. The abilities of other NDL-PCBs to inhibit store-operated Ca2+ entry (SOCE) were also examined and found to be of similar potencies to that of PCB19. PCB19 also showed a manner equivalent to that of known SOCE inhibitors. PCB19-mediated SOCE inhibition was confirmed by demonstrating the ability of PCB19 to inhibit the SOCE current and thapsigargin-induced Mn2+ influx. These results imply that one of the molecular mechanism by which NDL-PCBs cause neurobehavioral disturbances involves NDL-PCB-mediated inhibition of SOCE, thereby interfering with GPCR-mediated Ca2+ signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels / metabolism*
  • Calcium Signaling / drug effects*
  • Manganese / metabolism
  • PC12 Cells
  • Polychlorinated Biphenyls / toxicity*
  • Rats
  • Receptors, G-Protein-Coupled / metabolism*
  • Thapsigargin / pharmacology*

Substances

  • Calcium Channels
  • Receptors, G-Protein-Coupled
  • Manganese
  • Thapsigargin
  • Polychlorinated Biphenyls
  • Calcium

Grants and funding

This work was supported by the National Research Foundation of Korea (2015048003, 2013R1A2A2A01014688, 2013M3C7A1044016, http://www.nrf.re.kr/nrf_eng_cms/). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.