J Biol Chem. 2006 Jun 27; [Epub ahead of print]
Elevated testosterone induces apoptosis in neuronal cells.
Estrada M, Varshney A, Ehrlich BE.
Dept. of Pharmacology, Yale University, New Haven, CT 06520-8066.
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 mM to 10 mM)
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 InsP3R-mediated Ca2+ release. Knock down of
InsP3R type 1 with specific siRNA also abolished the testosterone-induced
cell death and the prolonged Ca2+ signals. In contrast, knock down of
InsP3R type 3 neither modified 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.