title: 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(3)R) 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.
authors.affiliation: The Kuvin Center for the Study of Infectious and Tropical Diseases, Department of Microbiology and Molecular Genetics, Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Feldmann
authors.forename: Michal
authors.initials: M
authors.lastname: Shahar
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.forename: David
authors.initials: D
authors.lastname: Lichtstein
authors.forename: Haim
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D017487:Ankyrins / Q000494:pharmacology; D002018:Bufanolides / Q000494:pharmacology; D019556:COS Cells; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D055785:Gene Knockdown Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010944:Plants; D034741:RNA, Small Interfering / Q000235:genetics; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins; D002018:Bufanolides; D002301:Cardiac Glycosides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D034741:RNA, Small Interfering; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D010042:Ouabain; C022777:bufalin