Atrial natriuretic peptide induces natriuretic peptide receptor-cGMP-dependent protein kinase interaction

Nathan Airhart, Yong Feng Yang, Charles Roberts, Gary (Michael) Silberbach

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)38693-38698
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
StatePublished - Oct 3 2003

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Cyclic GMP-Dependent Protein Kinases
Natriuretic Peptides
Peptide Receptors
Atrial Natriuretic Factor
Protein-Serine-Threonine Kinases
Ligands
Association reactions
Phosphorylation
Guanylate Cyclase
Cardiomegaly
Cell membranes
Gene Library
Yeast
Nitric Oxide
Yeasts
Chemical activation
Cell Membrane
Pharmacology
Hypertension

ASJC Scopus subject areas

  • Biochemistry

Cite this

Atrial natriuretic peptide induces natriuretic peptide receptor-cGMP-dependent protein kinase interaction. / Airhart, Nathan; Yang, Yong Feng; Roberts, Charles; Silberbach, Gary (Michael).

In: Journal of Biological Chemistry, Vol. 278, No. 40, 03.10.2003, p. 38693-38698.

Research output: Contribution to journalArticle

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