Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases

Abstract

ALPHA atrial natriuretic peptide (α-ANP) and brain natriuretic peptide are homologous polypeptide hormones involved in the regulation of fluid and electrolyte homeostasis^1,2. These two natriuretic peptides apparently share common receptors and stimulate the intracellular production of cyclic GMP as a second messenger¹. Molecular cloning has defined two types of natriuretic peptide receptors: the ANP-C receptor of relative molecular mass (M_r) 60–70,000 (60–70 K), which is not coupled to cGMP production and may function in the clearance of ANP (refs 3,4) and the ANP-A receptor of M_r 120–140 K, which is a membrane form of guanylate cyclase in which ligand binding to the extracellular domain activates the cytoplasmic domain of the enzyme^5,6. Here we report the cloning and expression of a second human natriuretic peptide-receptor guanylate cyclase, the ANP-B receptor. The ANP-B receptor is preferentially activated by porcine brain natriuretic peptide rather than human α-ANP, whereas the ANP-A receptor responds similarly to both natriuretic peptides. These observations may have important implications for our understanding of the central and peripheral control of cardiovascular homeostasis.