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Vol. 18, Issue 11, 4508-4518, November 2007

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Arrestins and Spinophilin Competitively Regulate Na⁺,K⁺-ATPase Trafficking through Association with a Large Cytoplasmic Loop of the Na⁺,K⁺-ATPase

Tohru Kimura^*, Patrick B. Allen, Angus C. Nairn, and Michael J. Caplan^*

Departments of *Cellular and Molecular Physiology and Psychiatry, Yale University School of Medicine, New Haven, CT 06520-8026

Submitted August 15, 2006; Revised July 31, 2007; Accepted August 28, 2007
Monitoring Editor: J. Silvio Gutkind

The activity and trafficking of the Na⁺,K⁺-ATPase are regulated by several hormones, including dopamine, vasopressin, and adrenergic hormones through the action of G-protein–coupled receptors (GPCRs). Arrestins, GPCR kinases (GRKs), 14-3-3 proteins, and spinophilin interact with GPCRs and modulate the duration and magnitude of receptor signaling. We have found that arrestin 2 and 3, GRK 2 and 3, 14-3-3 , and spinophilin directly associate with the Na⁺,K⁺-ATPase and that the associations with arrestins, GRKs, or 14-3-3 are blocked in the presence of spinophilin. In COS cells that overexpressed arrestin, the Na⁺,K⁺-ATPase was redistributed to intracellular compartments. This effect was not seen in mock-transfected cells or in cells expressing spinophilin. Furthermore, expression of spinophilin appeared to slow, whereas overexpression of -arrestins accelerated internalization of the Na⁺,K⁺-ATPase endocytosis. We also find that GRKs phosphorylate the Na⁺,K⁺-ATPase in vitro on its large cytoplasmic loop. Taken together, it appears that association with arrestins, GRKs, 14-3-3 , and spinophilin may be important modulators of Na⁺,K⁺-ATPase trafficking.

Address correspondence to: Michael Caplan (michael.caplan{at}yale.edu).

Abbreviations used: PKA, protein kinase A; PKC, protein kinase C; HA, hemagglutinin; GPCR, G-protein–coupled receptor; GRK, G-protein–coupled receptor kinase.

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