SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process

*Membrane Signaling Networks, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden;
^†Institut National de la Sante et de la Recherche Médicale, Unité 575, 67084 Strasbourg, France;
^‡Department of Medicine, University of Chicago, Chicago, IL 60637; and
^§Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation, Osaka 567-0085, Japan

Edited by Susan G. Amara, University of Pittsburgh School of Medicine, Pittsburgh, PA, and approved September 7, 2007 (received for review July 20, 2007)

Abstract

In mammalian cells, active sodium transport and its derived functions (e.g., plasma membrane potential) are dictated by the activity of the Na⁺,K⁺-ATPase (NK), whose regulation is essential for maintaining cell volume and composition, as well as other vital cell functions. Here we report the existence of a salt-inducible kinase-1 (SIK1) that associates constitutively with the NK regulatory complex and is responsible for increases in its catalytic activity following small elevations in intracellular sodium concentrations. Increases in intracellular sodium are paralleled by elevations in intracellular calcium through the reversible Na⁺/Ca²⁺ exchanger, leading to the activation of SIK1 (Thr-322 phosphorylation) by a calcium calmodulin-dependent kinase. Activation of SIK1 results in the dephosphorylation of the NK α-subunit and an increase in its catalytic activity. A protein phosphatase 2A/phosphatase methylesterase-1 (PME-1) complex, which constitutively associates with the NK α-subunit, is activated by SIK1 through phosphorylation of PME-1 and its dissociation from the complex. These observations illustrate the existence of a distinct intracellular signaling network, with SIK1 at its core, which is triggered by a monovalent cation (Na⁺) and links sodium permeability to its active transport.

Footnotes

^¶To whom correspondence should be addressed. E-mail: alejandro.bertorello{at}ki.se
Author contributions: M.S. and K.S. contributed equally to this work; K.S. and A.M.B. designed research; M.S., K.S., K.E., J.Z., H.T., and A.M.B. performed research; M.S., K.S., K.E., J.Z., A.I.K., H.T., and A.M.B. analyzed data; and K.S., K.E., A.I.K., and A.M.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706838104/DC1.
Abbreviations:

CaMK,

calmodulin-dependent protein kinase;

IP,

immunoprecipitated;

Mon,

monensin;

NCX,

Na+/Ca2+ exchanger;

NK,

Na+,K+-ATPase;

OK,

opossum kidney;

PME-1,

phosphatase methylesterase-1;

PPase,

protein phosphatase;

PP2A,

PPase 2A;

SIK1,

salt-inducible kinase 1;

WB,

Western blot.