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Am J Physiol Renal Physiol 295: F426-F437, 2008. First published June 11, 2008; doi:10.1152/ajprenal.00516.2007
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PTH-mediated regulation of Na+-K+-ATPase requires Src kinase-dependent ERK phosphorylation

Syed J. Khundmiri,1 Mohammed Ameen,1 Nicholas A. Delamere,2 and Eleanor D. Lederer1,3

1Department of Medicine, University of Louisville, Louisville, Kentucky; 2Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona; and 3Veterans Affairs Medical Center, Louisville, Kentucky

Submitted 5 November 2007 ; accepted in final form 4 June 2008

Parathyroid hormone (PTH) inhibits Na+-K+-ATPase activity by serine phosphorylation of the {alpha}1-subunit through ERK-dependent phosphorylation and translocation of protein kinase C{alpha} (PKC{alpha}). On the basis of previous studies, we postulated that PTH regulates sodium pump activity through Src kinase, PLC, and calcium-dependent ERK phosphorylation. In the present work utilizing opossum kidney cells, a model of renal proximal tubule, PTH-stimulated ERK phosphorylation and membrane translocation of PKC{alpha} were prevented by inhibition of Src kinase, PLC, and calcium entry. Pharmacological inhibition of PLA2 did not prevent PTH-stimulated ERK phosphorylation but completely prevented PKC{alpha} translocation. Silencing the expression of cytosolic or calcium-independent PLA2 also prevented PTH-mediated phosphorylation of Na+-K+-ATPase {alpha}1-subunit and PKC{alpha} without blocking ERK phosphorylation. Inhibition of Na+-K+-ATPase activity by the PLA2 metabolites arachidonic acid and 20-hydroxyeicosatetraenoic acid was prevented by specific inhibition of PKC{alpha} but not by U0126, a MEK-1 inhibitor. Transient transfection of constitutively active MEK-1 cDNA induced phosphorylation of Na+-K+-ATPase {alpha}1-subunit and PKC{alpha}, which was prevented by PLA2 inhibition. We conclude that PTH stimulates Na+-K+-ATPase phosphorylation and decreases the activity of Na+-K+-ATPase by a sequential activation of a signaling pathway involving Src kinase, PLC, ERK, PLA2, and PKC{alpha}.

Na+-K+-ATPase {alpha}1-subunit; parathyroid hormone; phospholipase C; extracellular signal-regulated kinase; phospholipase A2; protein kinase C{alpha}


Address for reprint requests and other correspondence: S. J. Khundmiri, Kidney Disease Program, Univ. of Louisville, 570 S. Preston St., Louisville, KY 40202 (e-mail: syed.khundmiri{at}louisville.edu)






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