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Department of Woman and Child Health and Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-11281 Stockholm, Sweden; and Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021
We have previously shown that the rat
Na+-K+-ATPase
1-isoform is phosphorylated at
Ser-943 by protein kinase A (PKA) and at Ser-23 by protein kinase C
(PKC), which in both cases results in inhibition of enzyme activity. We
now present evidence that suggests that the phosphorylation of Ser-943
by PKA modulates the response of
Na+-K+-ATPase
to PKC. Rat
Na+-K+-ATPase
1 or a mutant in which Ser-943
was changed to Ala-943 was stably expressed in COS cells. The
inhibition of enzyme activity measured in response to treatment with
the phorbol ester, phorbol 12,13-dibutyrate (PDBu;
10
6 M), was significantly
reduced in the cells expressing the Ala-943 mutant compared with that
observed in cells expressing wild-type enzyme. In contrast, for cells
expressing
Na+-K+-ATPase
1 in which Ser-943 was mutated
to Asp-943, the effect of PDBu was slightly enhanced. The PDBu-induced
inhibition was not mediated by activation of the adenosine
3',5'-cyclic monophosphate/PKA system and was not achieved
via direct phosphorylation of Ser-943. Sp-5,6-DCl-cBIMPS, a specific
PKA activator, increased the phosphorylation of Ser-943, and this was
associated with an enhanced response to PDBu. Thus the effect of PKC on
rat
Na+-K+-ATPase
1 is determined not only by the
activity of PKC but also by the state of phosphorylation of Ser-943.
adenosine 3',5'-cyclic monophosphate-dependent protein kinase; phorbol ester; COS cells; site-directed mutagenesis; protein kinase C
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