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J. Biol. Chem., Vol. 278, Issue 40, 38693-38698, October 3, 2003

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Atrial Natriuretic Peptide Induces Natriuretic Peptide Receptor-cGMP-dependent Protein Kinase Interaction^*

Nathan Airhart, Yong-Feng Yang, Charles T. Roberts, Jr. and Michael Silberbach 

From the Department of Pediatrics and the Heart Research Center, Oregon Health and Science University, Portland, Oregon 97239

Circulating natriuretic peptides such as atrial natriuretic peptide (ANP) counterbalance the effects of hypertension and inhibit cardiac hypertrophy by activating cGMP-dependent protein kinase (PKG). Natriuretic peptide binding to type I receptors (NPRA and NPRB) activates their intrinsic guanylyl cyclase activity, resulting in a rapid increase in cytosolic cGMP that subsequently activates PKG. Phosphorylation of the receptor by an unknown serine/threonine kinase is required before ligand binding can activate the cyclase. While searching for downstream PKG partners using a yeast two-hybrid screen of a human heart cDNA library, we unexpectedly found an upstream association with NPRA. PKG is a serine/threonine kinase capable of phosphorylating NPRA in vitro; however, regulation of NPRA by PKG has not been previously reported. Here we show that PKG is recruited to the plasma membrane following ANP treatment, an effect that can be blocked by pharmacological inhibition of PKG activation. Furthermore, PKG participates in a ligand-dependent gain-of-function loop that significantly increases the intrinsic cyclase activity of the receptor. PKG translocation is ANP-dependent but not nitric oxide-dependent. Our results suggest that anchoring of PKG to NPRA is a key event after ligand binding that determines distal effects. As such, the NPRA-PKG association may represent a novel mechanism for compartmentation of cGMP-mediated signaling and regulation of receptor sensitivity.

Received for publication, April 18, 2003 , and in revised form, July 1, 2003.

^* This work was supported by grants (to M. S.) from the Friends of Doernbecher, the Dickinson Family Foundation, and the Glenn and Juanita Struble Research Fund of the Oregon Health and Science University Heart Research Center. 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.

To whom correspondence should be addressed: Doernbecher Children's Hospital, 707 S.W. Gaines Rd., Mail Code CDRC-P, Portland, OR 97239-2901. Tel.: 503-494-9899; Fax: 503-494-2824; E-mail: silberbm{at}ohsu.edu.

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