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Am J Physiol Cell Physiol 277: C1202-C1209, 1999;
0363-6143/99 $5.00
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Vol. 277, Issue 6, C1202-C1209, December 1999

EDITORIAL FOCUS
Protein kinase D inhibits plasma membrane Na+/H+ exchanger activity

Robert S. Haworth1, James Sinnett-Smith2, Enrique Rozengurt2, and Metin Avkiran1

1 Centre for Cardiovascular Biology and Medicine, King's College London, London, United Kingdom; and 2 Department of Medicine, University of California Los Angeles School of Medicine and Molecular Biology Institute, Los Angeles, California

The regulation of plasma membrane Na+/H+ exchanger (NHE) activity by protein kinase D (PKD), a novel protein kinase C- and phorbol ester-regulated kinase, was investigated. To determine the effect of PKD on NHE activity in vivo, intracellular pH (pHi) measurements were made in COS-7 cells by microepifluorescence using the pH indicator cSNARF-1. Cells were transfected with empty vector (control), wild-type PKD, or its kinase-deficient mutant PKD-K618M, together with green fluorescent protein (GFP). NHE activity, as reflected by the rate of acid efflux (JH), was determined in single GFP-positive cells following intracellular acidification. Overexpression of wild-type PKD had no significant effect on JH (3.48 ± 0.25 vs. 3.78 ± 0.24 mM/min in control at pHi 7.0). In contrast, overexpression of PKD-K618M increased JH (5.31 ± 0.57 mM/min at pHi 7.0; P < 0.05 vs. control). Transfection with these constructs produced similar effects also in A-10 cells, indicating that native PKD may have an inhibitory effect on NHE in both cell types, which is relieved by a dominant-negative action of PKD-K618M. Exposure of COS-7 cells to phorbol ester significantly increased JH in control cells but failed to do so in cells overexpressing either wild-type PKD (due to inhibition by the overexpressed PKD) or PKD-K618M (because basal JH was already near maximal). A fusion protein containing the cytosolic regulatory domain (amino acids 637-815) of NHE1 (the ubiquitous NHE isoform) was phosphorylated in vitro by wild-type PKD, but with low stoichiometry. These data suggest that PKD inhibits NHE activity, probably through an indirect mechanism, and represents a novel pathway in the regulation of the exchanger.

pH regulation; COS-7; A-10; green fluorescent protein; sodium/hydrogen exchanger type 1; protein kinase Cµ


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