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Am J Physiol Cell Physiol 292: C1179-C1191, 2007. First published October 18, 2006; doi:10.1152/ajpcell.00328.2006
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CELLULAR METABOLISM

Multiplicity of expression of FXYD proteins in mammalian cells: dynamic exchange of phospholemman and -subunit in response to stress

¹Laboratory of Membrane Biology, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts; and ²Department of Pharmacology and Toxicology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico

Submitted 15 June 2006 ; accepted in final form 15 October 2006

Functional properties of Na-K-ATPase can be modified by association with FXYD proteins, expressed in a tissue-specific manner. Here we show that expression of FXYDs in cell lines does not necessarily parallel the expression pattern of FXYDs in the tissue(s) from which the cells originate. While being expressed only in lacis cells in the juxtaglomerular apparatus and in blood vessels in kidney, FXYD1 was abundant in renal cell lines of proximal tubule origin (NRK-52E, LLC-PK1, and OK cells). Authenticity of FXYD1 as a part of Na-K-ATPase in NRK-52E cells was demonstrated by co-purification, co-immunoprecipitation, and co-localization. Induction of FXYD2 by hypertonicity (500 mosmol/kgH₂O with NaCl for 48 h or adaptation to 700 mosmol/kgH₂O) correlated with downregulation of FXYD1 at mRNA and protein levels. The response to hypertonicity was influenced by serum factors and entailed, first, dephosphorylation of FXYD1 at Ser⁶⁸ (1–5 h) and, second, induction of FXYD2a and a decrease in FXYD1 with longer exposure. FXYD1 was completely replaced with FXYD2a in cells adapted to 700 mosmol/kgH₂O and showed a significantly decreased sodium affinity. Thus dephosphorylation of FXYD1 followed by exchange of regulatory subunits is utilized to make a smooth transition of properties of Na-K-ATPase. We also observed expression of mRNA for multiple FXYDs in various cell lines. The expression was dynamic and responsive to physiological stimuli. Moreover, we demonstrated expression of FXYD5 protein in HEK-293 and HeLa cells. The data imply that FXYDs are obligatory rather than auxiliary components of Na-K-ATPase, and their interchangeability underlies responses of Na-K-ATPase to cellular stress.

Na-K-ATPase; cellular stress; regulation

This article has been cited by other articles:

				I. Lubarski, S. J. D. Karlish, and H. Garty Structural and functional interactions between FXYD5 and the Na+-K+-ATPase Am J Physiol Renal Physiol, December 1, 2007; 293(6): F1818 - F1826. [Abstract] [Full Text] [PDF]