Natriuretic peptides and their receptors

Abstract

Natriuretic peptides secreted by the heart play a major role in the regulation of cardiovascular homeostasis and remodeling. This minireview series discusses physiological and pathophysiological roles of natriuretic peptides studied in animals and in humans, the structure and signaling mechanism of the receptors mediating peptides’ activities, and the metabolism of natriuretic peptides. The discovery of atrial natriuretic factor (or peptide) (ANP) by de Bold and associates 30 years ago has triggered many later studies, ranging from biochemistry, physiology and genetics to pathophysiology. It is now well established that ANP and the related B-type natriuretic peptide (BNP) play a major role in cardiovascular regulation through their natriuretic, diuretic and vasorelaxant activities, as well as their end-organ activities that suppress cardiac hypertrophy and fibrosis and cardiomyocyte apoptosis. These activities are mediated by the guanylate cyclase (GC)-linked natriuretic peptide receptor-A (NPRA, or GC-A). This ANP/BNP–NPRA signaling system is of major importance in cardiovascular homeostasis, counterbalancing the renin–angiotensin–aldosterone and neurohormonal systems. The physiology and pathophysiology of the ANP/BNP–NPRA system are reviewed here by Kishimoto et al. and by Pandey. The linkage to disease was first demonstrated in transgenic animals, where disruptions of the natriuretic peptide and receptor genes lead to, respectively, salt-sensitive essential hypertension and congestive heart failure accompanied by cardiac hypertrophy and fibrosis. Genetic studies involving very large human populations (as many as 150 000 individuals) have shown that variants within the ANP and BNP genes with reduced levels of circulating peptides are associated with elevated blood pressure - a potent risk factor for heart failure, stroke, myocardial infarction, and other major cardiovascular illnesses. Similar disease associations are found with variants in the receptor genes in humans. Clearly, the ANP/BNP–NPRA system presents an important target in cardiovascular disease therapy. At present, ANP and BNP are used as drugs (carperitide and nesiritide, respectively) for treating breathing difficulty in cases of acutely decompensated heart failure. However, because of their short plasma half-lives (minutes) following intravenous infusion, the effectiveness of these drugs are severely limited. Alternative, modified versions of the peptides are in development, such as chimeric natriuretic peptides with tailored activity profiles, protease-resistant peptides containing amino acid isosters, and peptide–serum albumin fusion proteins. Studies of natriuretic peptide metabolism, as reviewed by Potter, provide valuable guides for designing such peptides. Purification of the NPRA, first achieved from rat lung and bovine adrenal cortex, resulted in copurification of the ANP-binding and GC enzyme activities. Molecular cloning studies utilizing the known sequence homology in the nucleotide cyclase catalytic domains showed that the NPRA and related receptors, including the B-type natriuretic peptide receptor and the guanylin/enterotoxin receptor, constitute a family of GC-linked receptors (receptor-GCs). These receptors, along with receptor protein kinases, belong to the superfamily of enzyme-linked, single-transmembrane segment receptors. The crystal structures of the NPRA extracellular domain dimer with and without bound ANP have been determined (reviewed by Misono et al.). The structures show detailed receptor–ANP binding interactions, and a receptor-bound chloride possibly controlling the receptor allosterically within the renal tubule. The structures also reveal a novel ANP-induced rotation mechanism occurring in the juxtamembrane region that apparently triggers transmembrane signaling. The GC catalytic domain structures of Cyanobacter and green algae GCs recently reported are apparently consistent with the above mechanism. This rotation mechanism of receptor-GC signaling is in contrast with the dimerization (or association) mechanism mediating receptor protein kinase signaling. This minireview series summarizes representative aspects of the advances that have been made in understanding the roles and mechanisms of actions of natriuretic peptides and their receptors. In view of the important role of this regulatory system in cardiovascular physiology and pathophysiology, further advances are eagerly awaited for the betterment of cardiovascular disease therapy.