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J. Biol. Chem., Vol. 279, Issue 47, 48513-48519, November 19, 2004

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Calcium-dependent Dephosphorylation Mediates the Hyperosmotic and Lysophosphatidic Acid-dependent Inhibition of Natriuretic Peptide Receptor-B/Guanylyl Cyclase-B^*

Regine Potthast, Sarah E. Abbey-Hosch¶, Laura K. Antos, Jonathan S. Marchant||, Michaela Kuhn**, and Lincoln R. Potter||

From the Department of Biochemistry, Molecular Biology, and Biophysics and the ^||Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455 and ^**Institute of Pharmacology and Toxicology, Universitätsklinikum Münster, Domagkstrasse 12, D-48149 Münster, Germany

C-type natriuretic peptide binding to natriuretic peptide receptor-B (NPR-B) stimulates cGMP synthesis, which regulates vasorelaxation, cell proliferation, and bone growth. Here, we investigated the mechanistic basis for hyperosmotic and lysophosphatidic acid-dependent inhibition of NPR-B. Whole cell cGMP measurements and guanylyl cyclase assays indicated that acute hyperosmolarity decreased NPR-B activity in a reversible, concentration- and time-dependent manner, whereas chronic exposure had no effect. Acute hyperosmolarityelevatedintracellularcalciuminaconcentration-dependent fashion that paralleled NPR-B desensitization. A calcium chelator, but not a protein kinase C inhibitor, blocked both calcium elevations and desensitization. Hyperosmotic medium stimulated NPR-B dephosphorylation, and the receptor was rapidly rephosphorylated and resensitized when the hypertonic media was removed. Lysophosphatidic acid also inhibited NPR-B in a calcium- and phosphorylation-dependent process, consistent with calcium being a universal regulator of NPR-B. The absolute requirement of dephosphorylation in this process was demonstrated by showing that a receptor with glutamates substituted at all known NPR-B phosphorylation sites is unresponsive to hyperosmotic stimuli. This is the first study to measure the phosphorylation state of an endogenous guanylyl cyclase and to link intracellular calcium elevations with its dephosphorylation.

Received for publication, July 21, 2004 , and in revised form, September 10, 2004.

^* This work was supported in part by National Institutes of Health Grant RO1HL66397 and Scientist Development Award 0130398 from the National Division of the American Heart Association (to L. R. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Grant BMBF 01EC9801 from the German Bundesministerium fuer Forschung und Technik.

^¶ Supported by National Institutes of Health Training Grant AR07612.

To whom correspondence should be addressed: 6-155 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455. Tel.: 612-624-7251; Fax: 612-624-7282; E-mail: potter{at}umn.edu.

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