The Na +/Ca 2+-exchanger: An essential component in the mechanism governing cardiac steroid-induced slow Ca 2+ oscillations

Abstract

Plasma membrane (PM) Na +, K +-ATPase, plays crucial roles in numerous physiological processes. Cardiac steroids (CS), such as ouabain and bufalin, specifically bind to the Na +, K +-ATPase and affect ionic homeostasis, signal transduction, and endocytosed membrane traffic. CS-like compounds, synthesized in and released from the adrenal gland, are considered a new family of steroid hormones. Previous studies showed that ouabain induces slow Ca 2+ oscillations in COS-7 cells by enhancing the interactions between Na +, K +-ATPase, inositol 1,4,5-trisphosphate receptor (IP 3R) and Ankyrin B (Ank-B) to form a Ca 2+ signaling micro-domain. The activation of this micro-domain, however, is independent of InsP3 generation. Thus, the mechanism underlying the induction of these slow Ca 2+ oscillations remained largely unclear. We now show that other CS, such as bufalin, can also induce Ca 2+ oscillations. These oscillations depend on extracellular Ca 2+ concentrations [Ca 2+] out and are inhibited by Ni 2+. Furthermore, we found that these slow oscillations are Na + out dependent, abolished by Na +/Ca 2+ exchanger1 (NCX1)-specific inhibitors and markedly attenuated by NCX1 siRNA knockdown. Based on these results, a model is presented for the CS-induced slow Ca 2+ oscillations in COS-7 cells.