title: Non-Dioxin-Like Polychlorinated Biphenyls Inhibit G-Protein Coupled Receptor-Mediated Ca2+ Signaling by Blocking Store-Operated Ca2+ Entry.
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.
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Korea.|Department of Life Sciences, Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Korea.
authors.forename: Keimin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Yurim
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Physiology, Kangwon National University School of Medicine, Chuncheon, Korea.
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Jo
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Life Sciences, Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Korea.
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D008345:Manganese / Q000378:metabolism; D016716:PC12 Cells; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D043562:Receptors, G-Protein-Coupled; D008345:Manganese; D019284:Thapsigargin; D011078:Polychlorinated Biphenyls; D002118:Calcium