Document Detail

ortho-substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin-dependent mechanism.
MedLine Citation:
PMID:  11208908     Owner:  NLM     Status:  MEDLINE    
ortho-Substituted PCBs mobilize Ca2+ 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 [Ca2+]i and pH. RyR and IP3R share a common intracellular Ca2+ store in PC12 cells. Perfusion of nM to low microM PCB95 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 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 Ca2+ 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.
P W Wong; E F Garcia; I N Pessah
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  76     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2001 Jan 
Date Detail:
Created Date:  2002-07-23     Completed Date:  2002-08-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  450-63     Citation Subset:  IM    
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616, USA.
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MeSH Terms
Acidosis / chemically induced*
Bradykinin / pharmacology
Brain Chemistry
Calcium / metabolism
Calcium Signaling / drug effects*
Cell Respiration / drug effects
Enzyme Inhibitors / pharmacology
Estrogen Antagonists / pharmacology
Hydrogen-Ion Concentration / drug effects
Immunophilins / metabolism*
Inositol Phosphates / metabolism
Intracellular Fluid / drug effects,  metabolism
Mitochondria / chemistry,  drug effects
PC12 Cells
Pheochromocytoma / drug therapy,  metabolism*
Polychlorinated Biphenyls / pharmacology*
Rats, Sprague-Dawley
Ryanodine / pharmacology
Structure-Activity Relationship
Tacrolimus / pharmacology
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Estrogen Antagonists; 0/Inositol Phosphates; 0/Polychlorinated Biphenyls; 109581-93-3/Tacrolimus; 15662-33-6/Ryanodine; 38379-99-6/2,2',3,5',6-pentachlorobiphenyl; 57465-28-8/3,4,5,3',4'-pentachlorobiphenyl; 58-82-2/Bradykinin; 7440-70-2/Calcium; EC

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