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Contrary to Rat-Type, Human-Type Na,K-ATPase Is Phosphorylated at the Same Amino Acid by Hormones that Produce Opposite Effects on Enzyme Activity

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Texas

Address correspondence to: Dr. Riad Efendiev, University of Houston, College of Pharmacy, 4800 Calhoun Boulevard, Houston, TX 77204-5037; Phone: 713-743-1228; Fax: 713-743-1229; refendiev{at}uh.edu

Received for publication July 5, 2005. Accepted for publication October 11, 2005.

Renal sodium homeostasis is a major determinant of BP and is regulated by several natriuretic and antinatriuretic hormones. These hormones, acting through intracellular secondary messengers, either activate or inhibit proximal tubule Na,K-ATPase. It was shown previously that phorbol esters and angiotensin II and serotonin induce the phosphorylation of both Ser-11 and Ser-18 of the Na,K-ATPase -subunit. This results in the recruitment of Na,K-ATPase molecules to the plasma membrane and an increased capacity to transport sodium ions. Treatment of the same cells with dopamine leads to phosphorylation of the Na,K-ATPase -subunit Ser-18. The subsequent internalization of Na,K-ATPase molecules results in a reduced capacity to transport sodium ions. These effects are observed in cells that express the rat-type Na,K-ATPase. However, the Na,K-ATPase 1-subunit of several species, such as human, pig, and mouse, does not have a Ser-18 in their N-terminal region. Therefore, the possibility exists that, in those species, the Na,K-ATPase is not regulated by the hormones that regulate natriuresis. This study presents evidence that in cells that express the human-type Na,K-ATPase, dopamine inhibits and phorbol esters activate the Na,K-ATPase–mediated transport. These opposite effects are mediated by the phosphorylation of the same amino acid residue, Ser-11 of Na,K-ATPase 1, and the presence of 1 Ser-18 is not essential for the hormonal regulation of Na,K-ATPase activity in LLCPK1 cells. It was observed that, whereas the regulatory stimulation of Na,K-ATPase is mediated by protein kinase C, the regulatory inhibition is mediated by protein kinase C. This is similar to what was demonstrated previously in cells that express the rat-type Na,K-ATPase.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673