Molecular biology of the natriuretic peptide system: implications for physiology and hypertension.

The natriuretic peptides (NPs) are a group of peptide hormones that play important roles in the control of renal, cardiovascular, endocrine, and skeletal homeostasis. Atrial NP (ANP) was first identified as an activity by de Bold et al1 in 1981. It is a 28 amino acid peptide in humans that assumes a hairpin structure by virtue of a cystine bridge that links residues 7 and 23 (Figure 1). Brain NP (BNP), also known as the B-type NP, is 32 amino acids long in the human. It has a similar hairpin structure but demonstrates considerably more heterogeneity across species than ANP. C-type NP (CNP) is a 22 amino acid peptide that has a truncated carboxy terminus beyond the second cystine residue in the bridge. ANP and BNP are produced primarily within the muscle cells of the heart. ANP shows a preference for expression in the cardiac atria versus ventricle, whereas BNP is more equivalently expressed throughout the heart. ANP is also expressed in the hypothalamus where it is thought to control blood pressure (BP), sympathetic outflow, vasopressin secretion, drinking behavior, and cardiovascular homeostasis. BNP, on the other hand, is expressed in the brains of only a few species (eg, pig and dog), where its function remains unknown. CNP is expressed in the central nervous system, reproductive tract, bone, and endothelium of blood vessels. There are 3 different types of NP receptors, and each of them spans the membrane bilayer as a single transmembrane segment. The type A NP receptor (NPR-A) is also known as the particulate guanylyl cyclase A. It is the high affinity receptor for both ANP and BNP. A schematic of the structure of this receptor is presented in Figure 2. NPR-A has a glycosylated, extracellular, ligand-binding domain linked to a hydrophobic transmembrane spanning segment, a noncatalytic, ATP-binding, kinase-like domain in the proximal intracellular portion of the molecule, which is thought to function as a regulator of receptor activity, and a short hinge region. The NPR-A carboxy terminus contains the particulate guanylyl cyclase that is the catalytic effector of the receptor. Association of NPR-A with its cognate ligand (ANP or BNP) causes a conformational change in the kinase-like domain, which relaxes tonic inhibition of guanylyl cyclase activity and increases production of cGMP. NPR-B shares a similar structure with NPR-A. It binds selectively to CNP. NPR-C, the so-called clearance receptor, has an extracellular domain that is structurally homologous to that of the other NPRs. This is linked to a single transmembrane-spanning segment followed by an intracellular domain containing only 37 amino acids. NPR-C binds with high affinity to all 3 NPs, as well as to a variety of other peptides with more distant structural homology. The primary role of NPR-C is to function in a clearance mode, capturing and degrading NPs in the extracellular compartment.2 Earlier reviews have dealt with the regulators of NP gene expression.3 This brief review will focus on the molecular details underlying the transcriptional regulation of these genes and those of their receptors and the use of genetic models to dissect out their respective contributions to normal and abnormal cardiovascular and renal function.