Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert their physiological actions by binding to natriuretic peptide receptor A (N PRA), a receptor guanylate cyclase (rGC) that synthesizes cGMP in response to both ligands. The family of rGCs is rapidly expanding, and it is plausib le that there might be additional, as yet undiscovered, rGCs whose function is to provide alternative signalling pathways for one or both of these pep tides, particularly given the low affinity of NPRA for BNP. We have investi gated this hypothesis, using a genetically modified (knockout) mouse in whi ch the gene encoding NPRA has been disrupted. Enzyme assays and NPRA-specif ic Western blots performed on tissues from wild-type mice demonstrate that ANP-activated cGMP synthesis provides a good index of NPRA protein expressi on, which ranges from maximal in adrenal gland, lung, kidney, and testis to minimal in heart and colon. In contrast, immunoreactive NPRA is not detect able in tissues isolated from NPRA knockout animals and ANP- and BNP-stimul atable GC activities are markedly reduced in all mutant tissues. However, t estis and adrenal gland retain statistically significant, high-affinity res ponses to BNP. This residual response to BNP cannot be accounted for by nat riuretic peptide receptor B, or any other known mammalian rGC, suggesting t he presence of a novel receptor in these tissues that prefers BNP over ANP.