AGONIST SELECTIVITY FOR 3 SPECIES OF NATRIURETIC PEPTIDE RECEPTOR-A

We determined the nucleotide sequence of mouse natriuretic peptide rec eptor-A (NPR-A) cDNA and compared the revised deduced amino acid seque nce with those of rat and human NPR-A. The ligand selectivity of these three receptor/guanylyl cyclases was examined by whole-cell stimulati on of cGMP production. The 28-amino acid atrial natriuretic peptide (A NP) 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 ED(50) 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, dis ulfide-bonded ring of ANP and to the species differences in brain natr iuretic peptide (BNP) but is more sensitive to deletions in the carbox yl tail of ANP. The ANP determinants of agonist potency have therefore changed for different species of NPR-A. This is reflected in the amin o acid sequence divergence in the receptor extracellular domains and i n the divergence and specificity of BNP among species. Our results sug gest that the coevolution of NPR-A and BNP has thus been constrained w ithin the context of the conserved ANP sequence.