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Testosterone Induces an Intracellular Calcium Increase by a Nongenomic Mechanism in Cultured Rat Cardiac Myocytes

Centro de Estudios Moleculares de la Célula (J.M.V., C.I., M.E., M.C., D.S., V.P., G.D.-A., E.J., S.L.), Instituto de Ciencias Biomedicas (M.E., E.J., S.L.), Facultad de Medicina, and Facultad de Ciencias Quimicas y Farmaceuticas (J.M.V., C.I., M.C., D.S., V.P., G.D.-A., S.L.), Universidad de Chile, Santiago 6640750, Chile

Address all correspondence and requests for reprints to: Drs. Sergio Lavandero or Enrique Jaimovich, Centro FONDAP (Fondo de Invesigación Avanzada en Areas Prioritarias) Estudios Moleculares de la Celula, Universidad de Chile, Olivos 1007, Santiago 6640750, Chile. E-mail: slavander{at}uchile.cl; or ejaimovi{at}med.uchile.cl.

Androgens are associated with important effects on the heart, such as hypertrophy or apoptosis. These responses involve the intracellular androgen receptor. However, the mechanisms of how androgens activate several membrane signaling pathways are not fully elucidated. We have investigated the effect of testosterone on intracellular calcium in cultured rat cardiac myocytes. Using fluo3-AM and epifluorescence microscopy, we found that exposure to testosterone rapidly (1–7 min) led to an increase of intracellular Ca²⁺, an effect that persisted in the absence of external Ca²⁺. Immunocytochemical analysis showed that these effects occurred before translocation of the intracellular androgen receptor to the perinuclear zone. Pretreatment of the cells with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethylester and thapsigargin blocked this response, suggesting the involvement of internal Ca²⁺ stores. U-73122, an inhibitor of phospholipase C, and xestospongin C, an inhibitor of inositol 1,4,5-trisphosphate receptor, abolished the Ca²⁺ signal. The rise in intracellular Ca²⁺ was not inhibited by cyproterone, an antagonist of intracellular androgen receptor. Moreover, the cell impermeant testosterone-BSA complex also produced the Ca²⁺ signal, indicating its origin in the plasma membrane. This effect was observed in cultured neonatal and adult rat cardiac myocytes. Pertussis toxin and the adenoviral transduction of ß- adrenergic receptor kinase carboxy terminal peptide, a peptide inhibitor of ß-subunits of G protein, abolished the testosterone-induced Ca²⁺ release. In summary, this is the first study of rapid, nongenomic intracellular Ca²⁺ signaling of testosterone in cardiac myocytes. Using various inhibitors and testosterone-BSA complex, the mechanism for the rapid, testosterone-induced increase in intracellular Ca²⁺ is through activation of a plasma membrane receptor associated with a Pertussis toxin-sensitive G protein-phospholipase C/inositol 1,4,5-trisphosphate signaling pathway.

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