ortho-Substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin-dependent mechanism

ortho-Substituted PCBs mobilize Ca2+ from isolated brain microsomes by inte raction with FKBP12/RyR complexes. investigation into the cellular importan ce of this mechanism was undertaken using PC12 cells by fluoroimaging the a ctions of specific PCB congeners on [Ca2+](i) and pH. RyR and IP3R share a common intracellular Ca2+ store in PC12 cells. Perfusion of nM to low muM P CB95 caused a transient rise of [Ca2+](i) that was not completely dependent on extracellular Ca2+. Pre-incubation of the cells with ryanodine or FK506 completely eliminated PCB95 responses, suggesting a primary action on the FKPP12/RyR-sensitive store. PCB95, but not PCB126, induced a gradual decrea se in cytosolic pH that could be completely eliminated by FK506 pre-incubat ion of the cells. Direct respiration measurement using isolated brain mitoc hondria demonstrated that neither of the PCBs directly altered any stage of mitochondrial respiration. These results revealed that PCB95 disrupts intr acellular Ca2+ signaling in PC12 cells by interaction with the FKBP12/RyR c omplex that in turn accelerated cellular metabolism, possibly affecting sig naling between ER and mitochondria. Since ortho-substituted PCBs have been shown to be neurotoxic and may affect neurodevelopment, studies on the mole cular mechanism by which they alter cellular signaling may provide valuable information on the physiological roles of FKPB12 and RyR on neuronal funct ions.