The natriuretic peptides (NPs) hormone family, which consists mainly of atrial, brain, and C-type NPs (ANP, BNP, and CNP), play diverse roles in mammalian species, ranging from renal, cardiac, endocrine, neural, and vascular hemodynamics to metabolic regulations, immune responsiveness, and energy distributions. Over the last four decades, new data has transpired regarding the biochemical and molecular compositions, signaling mechanisms, and physiological and pathophysiological functions of NPs and their receptors. NPs are incremented mainly in eliciting natriuretic, diuretic, endocrine, vasodilatory, and neurological activities, along with antiproliferative, antimitogenic, antiinflammatory, and antifibrotic responses. The main locus responsible in the biological and physiological regulatory actions of NPs (ANP and BNP) is the plasma membrane guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), a member of the growing multi-limbed GC family of receptors. Advances in this field have provided tremendous insights into the critical role of Npr1 (encoding GC-A/NPRA) in the reduction of fluid volume and blood pressure homeostasis, protection against renal and cardiac remodeling, and moderation and mediation of neurological disorders. The generation and use of genetically engineered animals, including gene-targeted (gene-knockout and gene-duplication) and transgenic mutant mouse models has revealed and clarified the varied roles and pleiotropic functions of GC-A/NPRA in vivo in intact animals. This review provides a chronological development of the biochemical, molecular, physiological, and pathophysiological functions of GC-A/NPRA, including signaling pathways, genomics, and gene regulation in both normal and disease states.
A pioneering and innovative discovery by de Bold and colleagues four decades ago, found natriuretic and diuretic activity in the heart atrium extract, leading to the purification and characterization of atrial natriuretic factor/peptide (ANF/ANP). This discovery revealed a new natriuretic peptide (NP) hormone family and established that the heart is an endocrine organ. ANF/ANP exhibits diuretic, natriuretic, vasorelaxant, neurotransmission, antimitogenic, and anti-inflammatory responses directed largely toward the reduction of blood pressure (BP) and protection against renal and cardiovascular disorders. After the discovery of ANP, other members of this family were isolated and characterized, including brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), Dendroaspis natriuretic peptide or D-type NP (DNP), and urodilatin (URO). All NPs show similar biochemical, structural, and pharmacological characteristics, with a common 17-amino acid disulfide-bonded ring. Interestingly, each member of the NP hormone family seems to be derived from a separate gene. These peptides bind to different cognate receptors, exhibit distinct biological functions, and have varying sites of synthesis. ANP and BNP are predominantly produced in the cardiac atrium and ventricle, released in the plasma, and exhibit a high variation in sequence structure, whereas CNP is mainly synthesized in the brain and endothelial cells and is highly preserved across the species. DNP is predominantly synthesized in the venom of the green mamba (Dendroaspis angusticeps), and URO is produced in the kidney and secreted in the urine.
ANP plays a much wider and more significant role, particularly in hypertension and cardiovascular diseases. Both pro-ANP and pro-BNP genes (Nppa and Nppb) are also expressed in extra-cardiac tissues and cells, which seem to act in endocrine, autocrine, paracrine, and/or neurocrine manners. ANP targets the inhibition of aldosterone secretion from the adrenal glands, release of renin from the kidney, and vasopressin release from the posterior pituitary. ANP also stimulates the release of testosterone from normal Leydig cells, luteinizing hormone from the anterior pituitary gland, and progesterone from granulosa-luteal cells. BNP displays functions similar to ANP, but BNP also acts as a neurohormone and is preserved in the transient receptor potential vanilloid-1 (TRPV-1) in response to itch-inducing factors. DNP consists of 38 amino acid residues, however, its function has not yet been clearly established. URO is a 32-residues peptide hormone similar to the carboxyl-terminal sequence of pro-ANP, which was isolated and characterized from urine. It is believed that URO is largely synthesized in the kidneys but mostly absent in the circulation. Interestingly, URO is very resistant to proteolysis by endopeptidases and has an important role in the regulation of kidney function; more specifically, it controls the excretion of sodium and water, much like ANP and BNP.
The pharmacological and physiological functions of NPs is elicited through the binding of cognate plasma membrane receptor proteins. Three distinct subtypes of NPs receptor proteins have been identified and characterized: guanylyl cyclase (GC)/NP receptor-A (GC-A/NPRA), GC/NP receptor-B (GC-B/NPRB), and NP receptor-C (NPRC), encoded by specific genes, including Npr1, Npr2, and Npr3, respectively. Both ANP and BNP activate GC-A/NPRA, also known as GC-A receptor, which responds to hormone binding by producing intracellular second messenger cGMP to this receptor molecule. CNP specifically activates GC-B/NPRB, known as GC-B receptor, and also produces a second messenger, cGMP. All three NPs (ANP, BNP, and CNP) invariably bind to NPRC, which lacks an intracellular GC region. The prevalence of structurally related NPs and their three distinct receptors suggests that their role in physiological and pathophysiological control of BP, body fluid homeostasis, and metabolic regulation is complex. At the minimum, three distinct subtypes of effector molecules are prevalent: cGMP-dependent protein kinases (PKGs), cGMP-dependent phosphodiesterases (PDs), and cyclic-nucleotide gated ion channels (CNGs), which catalyze and amplify the signaling cascade of NP-specific cognate receptors.
In essence, GC-A/NPRA acts as the main functional receptor protein for both ANP and BNP; and in a large part, the biological and physiological functions of hormones are discharged by the production of intracellular generation cGMP.
