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Articles in PresS, published online ahead of print April 2, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00206.2001
Submitted on July 2, 2001
Accepted on March 27, 2002
1 Department of Physiology, University of Wuerzburg, Wuerzburg, Germany
2 Aventis Company, Frankfurt, Germany
3 Department of Cell Biology, University of Aarhus, Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: michael.gekle{at}mail.uni-wuerzburg.de.
Receptor-mediated, clathrin-dependent endocytosis (RME) is important for macromolecule transport and regulation of cell-surface protein expression. Pharmacological studies have shown that the plasma membrane transport protein Na+/H+-exchange-3 (NHE-3), which shuttles between the plasma membrane and the early endosomal compartment via clathrin-mediated endocytosis, contributes to endosomal pH-homeostasis and endocytic fusion events. Furthermore, it is known that NHE-3 is phosphorylated and inhibited by cAMP-dependent kinase (PKA). Here we show, in a cellular knock-out/retransfection approach, that NHE-3 supports RME and confers cAMP-sensitivity to RME, using megalin/cubilin-mediated albumin uptake in Opossum-Kidney(OK)-cells. RME, but not fluid-phase endocytosis, was dependent on NHE-3 activity and expression. Furthermore, NHE-3-deficiency or -inhibition reduced the relative surface expression of megalin without altering total expression. In wild type cells cAMP inhibits NHE-3 activity, leads to endosomal alkalinization and reduces RME. In NHE-3 deficient cells, endosomal pH is not sensitive to NHE-3 inhibition and cAMP does not affect endosomal pH nor RME. NHE-3 transfection into deficient cells restores RME and the cAMP-effects. Thus, our data show that NHE-3 is important for cAMP-sensitivity of clathrin-dependent RME.
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