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ortho ‐Substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin‐dependent mechanism
Author(s) -
Wong Patty W.,
Garcia Eric F.,
Pessah Isaac N.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00022.x
Subject(s) - ryanodine receptor , intracellular , cytosol , extracellular , microbiology and biotechnology , mitochondrion , calcium signaling , calcium in biology , calcium , incubation , biology , signal transduction , fkbp , cellular respiration , biochemistry , chemistry , biophysics , enzyme , organic chemistry
ortho ‐Substituted PCBs mobilize Ca 2+ from isolated brain microsomes by interaction with FKBP12/RyR complexes. Investigation into the cellular importance of this mechanism was undertaken using PC12 cells by fluoroimaging the actions of specific PCB congeners on [Ca 2+ ] i and pH. RyR and IP 3 R share a common intracellular Ca 2+ store in PC12 cells. Perfusion of nM to low µM PCB95 caused a transient rise of [Ca 2+ ] i that was not completely dependent on extracellular Ca 2+ . 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 decrease in cytosolic pH that could be completely eliminated by FK506 pre‐incubation of the cells. Direct respiration measurement using isolated brain mitochondria demonstrated that neither of the PCBs directly altered any stage of mitochondrial respiration. These results revealed that PCB95 disrupts intracellular Ca 2+ signaling in PC12 cells by interaction with the FKBP12/RyR complex that in turn accelerated cellular metabolism, possibly affecting signaling between ER and mitochondria. Since ortho ‐substituted PCBs have been shown to be neurotoxic and may affect neurodevelopment, studies on the molecular mechanism by which they alter cellular signaling may provide valuable information on the physiological roles of FKPB12 and RyR on neuronal functions.