Distinct role of the N-terminal tail of the Na,K-ATPase catalytic subunit as a signal transducer

Abstract

Mounting evidence suggests that the ion pump, Na,K-ATPase, can, in the presence of ouabain, act as a signal transducer. A prominent binding motif linking the Na,K-ATPase to intracellular signaling effectors has, however, not yet been identified. Here we report that the N-terminal tail of the Na,K-ATPase catalytic α-subunit (αNT-t) binds directly to the N terminus of the inositol 1,4,5-trisphosphate receptor. Three amino acid residues, LKK, conserved in most species and most α-isoforms, are essential for the binding to occur. In wild-type cells, low concentrations of ouabain trigger low frequency calcium oscillations that activate NF-κB and protect from apoptosis. All of these effects are suppressed in cells overexpressing a peptide corresponding to αNT-t but not in cells overexpressing a peptide corresponding to αNT-tΔLKK. Thus we have identified a well conserved Na,K-ATPase motif that binds to the inositol 1,4,5-trisphosphate receptor and can trigger an anti-apoptotic calcium signal. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.