Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab -/- mice.
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.
Department of Pharmacology, University of Minnesota, Twin Cities, 321 Church St SE, Minneapolis, MN 55455, USA. yoder013@umn.edu
Andrea R
AR
Yoder
Andrew C
AC
Kruse
Cathleen A
CA
Earhart
Douglas H
DH
Ohlendorf
Lincoln R
LR
Potter
D000595:Amino Acid Sequence; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004392:Dwarfism / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D020098:Natriuretic Peptide, C-Type / Q000502:physiology*; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology*; D000099242:Atrial Natriuretic Factor Receptor B
D006152:Cyclic GMP; D020098:Natriuretic Peptide, C-Type; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B