Elevated testosterone induces apoptosis in neuronal cells.
* Estrada M,
* Varshney
A,
* Ehrlich BE.
Department of Pharmacology and Cellular and Molecular Physiology, Yale University, New
Haven, Connecticut 06520,
USA.iestrada@med.uchile.cl
Testosterone plays a crucial role in
neuronal function, but elevated concentrations can have deleterious effects. Here we show that supraphysiological
levels of testosterone (micromolar range) initiate the apoptotic cascade. We used three criteria, annexin V
labeling, caspase activity, and DNA fragmentation, to determine that apoptotic pathways were activated by
testosterone. Micromolar, but not nanomolar, testosterone concentrations increased the response in all three assays
of apoptosis. In addition, testosterone induced different concentration-dependent Ca2+ signaling patterns: at low
concentrations of testosterone (100 nm), Ca2+ oscillations were produced, whereas high concentrations (1-10 microm)
induced a sustained Ca2+ increase. Elevated testosterone concentrations increase cell death, and this effect was
abolished in the presence of either inhibitors of caspases or the inositol 1,4,5-trisphosphate receptor
(InsP3R)-mediated Ca2+ release. Knockdown of InsP3R type 1 with specific small interfering RNA also abolished the
testosterone-induced cell death and the prolonged Ca2+ signals. In contrast, knockdown of InsP3R type 3 modified
neither the apoptotic response nor the Ca2+ signals. These results support our hypothesis that elevated testosterone
alters InsP3R type 1-mediated intracellular Ca2+ signaling and that the prolonged Ca2+ signals lead to apoptotic
cell death. These effects of testosterone on neurons will have long term effects on brain function.
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