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

Andrea R. Yoder, Andrew C. Kruse, Cathleen A. Earhart, Douglas H. Ohlendorf, Lincoln R. Potter

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 CNPlbab 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 CNPlbab to activate NPR-B was explained, at least in part, by decreased binding since 10-fold more CNPlbab 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.

Original languageEnglish (US)
Pages (from-to)1575-1581
Number of pages7
JournalPeptides
Volume29
Issue number9
DOIs
StatePublished - Sep 2008

Bibliographical note

Funding Information:
This work was funded by grants from the University of Minnesota Medical School, NIH grant (AI057585) to CAE, and a grant-in-aid from the Graduate School of the University of Minnesota. ARY was supported in part by a fellowship from the 3M Corporation.

Keywords

  • Cyclic-GMP
  • Endochondrial ossification
  • Guanylyl cyclase B
  • Nppc
  • Type II cGMP dependant protein kinase

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