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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 43; pp. 16922 - 16927
• Main Authors: Sjöström, Mattias, Stenström, Karin, Eneling, Kristina, Zwiller, Jean, Katz, Adrian I, Takemori, Hiroshi, Bertorello, Alejandro M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.10.2007; National Acad Sciences
• Subjects: Adenosine triphosphatase; Animals; Antibodies; Biochemistry; Biological Sciences; Biological Transport, Active - drug effects; Calcium; Calcium - metabolism; Calcium Signaling - drug effects; Carboxylic Ester Hydrolases - metabolism; Catalysis - drug effects; Catalytic activity; Cell free system; Cell Line; Cell membranes; Cells; Enzyme Activation - drug effects; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Hep G2 cells; Humans; Ion Transport - drug effects; Kidney - cytology; Kidney - drug effects; Kidney - enzymology; Kinases; Medicin och hälsovetenskap; Molecules; Opossums; Phosphatases; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Phosphorylation - drug effects; Physiological regulation; Protein Binding - drug effects; Protein Phosphatase 2 - metabolism; Protein Subunits - metabolism; Protein-Serine-Threonine Kinases - metabolism; Sodium; Sodium - metabolism; Sodium - pharmacology; Sodium-Potassium-Exchanging ATPase - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0706838104

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.