Distinct role of the N-terminal tail of the Na,K-ATPase catalytic subunit as a signal transducer.
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 alpha-subunit (alphaNT-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 alpha-isoforms, are essential for the binding to occur. In wild-type cells, low concentrations of ouabain trigger low frequency calcium oscillations that activate NF-kappaB and protect from apoptosis. All of these effects are suppressed in cells overexpressing a peptide corresponding to alphaNT-t but not in cells overexpressing a peptide corresponding to alphaNT-t deltaLKK. 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.
Zhang
Songbai
S
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Q2:09, SE-171 76 Stockholm, Sweden; Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Malmersjö
Seth
S
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Q2:09, SE-171 76 Stockholm, Sweden.
Li
Juan
J
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Q2:09, SE-171 76 Stockholm, Sweden.
Ando
Hideaki
H
Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Laboratory for Developmental Neurobiology, Brain Science Institute, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Aizman
Oleg
O
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Q2:09, SE-171 76 Stockholm, Sweden.
Uhlén
Per
P
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Q2:09, SE-171 76 Stockholm, Sweden.
Mikoshiba
Katsuhiko
K
Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Laboratory for Developmental Neurobiology, Brain Science Institute, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Aperia
Anita
A
Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Q2:09, SE-171 76 Stockholm, Sweden. Electronic address: anita.aperia@ki.se.
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002384:Catalysis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; C025389:Itpr1 protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D010042:Ouabain; C499076:ATP1A1 protein, human; C499075:Atp1a1 protein, rat; C497344:Atp1a1 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase