Chronic reduction in complex I function alters calcium signaling in SH-SY5Y neuroblastoma cells.
Sporadic, non-familial Parkinson's disease is characterized by a 15-30% reduction in complex I activity of the electron transport chain. A pharmacological model of reduced complex I activity was created by prolonged treatment of SH-SY5Y cells with low doses (5-20 nM) of rotenone, a selective inhibitor of complex I. Short-term (less than 2 week) exposure to rotenone did not influence calcium signaling, production of reactive oxygen species, or mitochondrial morphology. However, following 2 weeks of rotenone exposure, SH-SY5Y cells showed unusual calcium dynamics, specifically multiple calcium responses to carbachol, a muscarinic agonist. These secondary calcium responses were not seen in control SH-SY5Y cells and were dependent upon calcium influx. Mitochondrial membrane potential was also reduced in low dose rotenone-treated cells. These results demonstrate that a chronic, partial reduction in complex I activity, such as that seen in Parkinson's disease, can alter cell signaling events and perhaps increase the susceptibility of cells to calcium overload and subsequent cell death.
Sherer
T B
TB
Department of Neurology, Emory University, Atlanta, GA, USA.
Trimmer
P A
PA
Borland
K
K
Parks
J K
JK
Bennett
J P
JP
Tuttle
J B
JB
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D042967:Electron Transport Complex I; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000201:enzymology / Q000503:physiopathology; D009447:Neuroblastoma; D010300:Parkinson Disease / Q000201:enzymology* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology*; D014475:Uncoupling Agents / Q000494:pharmacology
D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I