Agonist selectivity for three species of natriuretic peptide receptor-A.
We determined the nucleotide sequence of mouse natriuretic peptide receptor-A (NPR-A) cDNA and compared the revised deduced amino acid sequence with those of rat and human NPR-A. The ligand selectivity of these three receptor/guanylyl cyclases was examined by whole-cell stimulation of cGMP production. The 28-amino acid atrial natriuretic peptide (ANP) has only one difference among these three species, i.e., human Met-12 versus rat and mouse Ile-12. However, despite the nearly invariant ANP sequence among these species, ANP analogs have marked differences in ED50 values and maximal cGMP responses among the three receptors. With the natriuretic peptide analogs we tested, human NPR-A is less sensitive than rat or mouse NPR-A to changes in the 17-amino acid, disulfide-bonded ring of ANP and to the species differences in brain natriuretic peptide (BNP) but is more sensitive to deletions in the carboxyl tail of ANP. The ANP determinants of agonist potency have therefore changed for different species of NPR-A. This is reflected in the amino acid sequence divergence in the receptor extracellular domains and in the divergence and specificity of BNP among species. Our results suggest that the coevolution of NPR-A and BNP has thus been constrained within the context of the conserved ANP sequence.
Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080.
J R
JR
Schoenfeld
P
P
Sehl
C
C
Quan
J P
JP
Burnier
D G
DG
Lowe
D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D006162:Guanylate Cyclase / Q000819:agonists* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000819:agonists* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A