Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab -/- mice.

Abstract

C-type natriuretic peptide (CNP) stimulates endochondrial ossification by activating the transmembrane guanylyl cyclase, natriuretic peptide receptor-B (NPR-B). Recently, a spontaneous autosomal recessive mutation that causes severe dwarfism in mice was identified. The mutant, called long bone abnormality (lbab), contains a single point mutation that converts an arginine to a glycine in a conserved coding region of the CNP gene, but how this mutation affects CNP activity has not been reported. Here, we determined that 30-fold to greater than 100-fold more CNP(lbab) was required to activate NPR-B as compared to wild-type CNP in whole cell cGMP elevation and membrane guanylyl cyclase assays. The reduced ability of CNP(lbab) to activate NPR-B was explained, at least in part, by decreased binding since 10-fold more CNP(lbab) than wild-type CNP was required to compete with [125I][Tyr0]CNP for receptor binding. Molecular modeling suggested that the conserved arginine is critical for binding to an equally conserved acidic pocket in NPR-B. These results indicate that reduced binding to and activation of NPR-B causes dwarfism in lbab(-/-) mice.

• Authors: Andrea R Yoder, Andrew C Kruse, Cathleen A Earhart, Douglas H Ohlendorf, Lincoln R Potter
• Journal: Peptides (Peptides) Vol. 29 Issue 9 Pg. 1575-81 (Sep 2008) ISSN: 0196-9781 [Print] United States
• PMID: 18554750 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Natriuretic Peptide, C-Type
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor B
• Cyclic GMP

Topics

• Amino Acid Sequence
• Animals
• Cyclic GMP (metabolism)
• Dwarfism (etiology, genetics)
• Mice
• Mice, Mutant Strains
• Models, Molecular
• Natriuretic Peptide, C-Type (physiology)
• Receptors, Atrial Natriuretic Factor (physiology)