Protein Phosphatase 2A Interacts with the Na ⁺,K ⁺-ATPase and Modulates Its Trafficking by Inhibition of Its Association with Arrestin

Abstract

Background

The P-type ATPase family constitutes a collection of ion pumps that form phosphorylated intermediates during ion transport. One of the best known members of this family is the Na ⁺,K ⁺-ATPase. The catalytic subunit of the Na ⁺,K ⁺-ATPase includes several functional domains that determine its enzymatic and trafficking properties.

Methodology/Principal Findings

Using the yeast two-hybrid system we found that protein phosphatase 2A (PP2A) catalytic C-subunit is a specific Na ⁺,K ⁺-ATPase interacting protein. PP-2A C-subunit interacted with the Na ⁺,K ⁺-ATPase, but not with the homologous sequences of the H ⁺,K ⁺-ATPase. We confirmed that the Na ⁺,K ⁺-ATPase interacts with a complex of A- and C-subunits in native rat kidney. Arrestins and G-protein coupled receptor kinases (GRKs) are important regulators of G-protein coupled receptor (GPCR) signaling, and they also regulate Na ⁺,K ⁺-ATPase trafficking through direct association. PP2A inhibits association between the Na ⁺,K ⁺-ATPase and arrestin, and diminishes the effect of arrestin on Na ⁺,K ⁺-ATPase trafficking. GRK phosphorylates the Na ⁺,K ⁺-ATPase and PP2A can at least partially reverse this phosphorylation.

Conclusions/Significance

Taken together, these data demonstrate that the sodium pump belongs to a growing list of ion transport proteins that are regulated through direct interactions with the catalytic subunit of a protein phosphatase.