Capacitative calcium entry contributes to nuclear factor of activated T-cells nuclear translocation and hypertrophy in cardiomyocytes

In nonexcitable cells, depletion of endoplasmic reticulum Ca2+ stores leads to activation of plasma membrane Ca2+ channels, a process termed capacitative Ca2+ entry. Here, we demonstrate that this pathway functions in cells that also contain voltage-gated Ca2+ channels, neonatal rat ventricular myocytes. The depletion of sarcoplasmic reticulum Ca2+ stores elicited a prolonged increase in cytoplasmic Ca2+ dependent on extracellular Ca2+. Inhibitors of store-operated channels but not L-type channels diminished this response. The importance of this pathway to cardiac hypertrophy, which often is dependent on Ca2+/calmodulin-dependent transcription factors, was also assessed in this model. Hypertrophy and atrial natriuretic factor expression induced by angiotensin II or phenylephrine was more effectively attenuated by inhibitors of capacitative entry than of L-type channels. Additionally, cardiomyocytes were transfected with a construct encoding a fluorescent nuclear factor of activated T-cells chimeric protein to follow nuclear localization in response to thapsigargin, angiotensin II, and phenylephrine. This translocation was completely prevented by inhibitors of capacitative Ca2+ entry and only partially abrogated by inhibitors of L-type channels. In contrast, a hypertrophic response induced by overexpression of the transcription factor MEK1 was unaffected by inhibitors of capacitative entry. Together, these data suggest a role for CCE in cardiomyocyte physiology and, in particular, in Ca2+-mediated cardiac hypertrophy.