Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation

Abstract

Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide (ANP), is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and anti-proliferative effects, which are important in the control of blood pressure and cardiovascular events. One principal locus involved in the regulatory action of ANP and brain natriuretic peptide (BNP) is guanylyl cyclase / natriuretic peptide receptor-A (GC-A/NPRA). Studies on ANP, BNP, and their receptor, GC-A/NPRA, have greatly increased our knowledge of the control of hypertension and cardiovascular disorders. Cellular, biochemical, and molecular studies have helped to delineate the receptor function and signaling mechanisms of NPRA. Gene-targeted and transgenic mouse models have advanced our understanding of the importance of ANP, BNP, and GC-A/NPRA in disease states at the molecular level. Importantly, ANP and BNP are used as critical markers of cardiac events; however, their therapeutic potentials for the diagnosis and treatment of hypertension, heart failure, and stroke have just begun to be realized. We are now just at the initial stage of molecular therapeutics and pharmacogenomic advancement of the natriuretic peptides. More investigations should be undertaken and ongoing ones be extended in this important field.

Figure 1. Comparison of amino acid sequence of the natriuretic peptide hormone family

Comparison of amino-acid sequence of human ANP, BNP, and CNP with conserved amino acid residues, which are represented by shaded boxes. The lines between two cysteine residues in ANP, BNP, and CNP indicate a 17-amino acid disulfide bridge, which is essential for the biological activity of three natriuretic peptide hormones. ANF, atrial natriuretic peptide; BNP, brain natriuretic peptide; and CNP, C-type natriuretic peptide.

Figure 2. Diagrammatic representation of the structural features of guanylyl cyclase/natriuretic peptide receptor-A cDNA sequence

The hutched portions of the bar represent the coding region of murine cDNA sequence and the solid areas of the bar represent the untranslated regions at the 5'- and 3'- ends, respectively. The major restriction sites are shown above the hatched bar, representating the coding region of cDNA sequence. The brackets at the bottom of hatched portions of coding region, indicate the extracellular ANP binding domain (469 amino acids) and intracellular protein kinase-like domain as well as guanylyl cyclase catalytic domain (567 amino acids). The solid portions at beginning of coding region represents 28 amino acid signal sequence and in the middle of the coding region it represents 21 amino acid transmembrane domain. Seven glycosylation sites are present in the extracellular domain and two glycosylation sites are present in the intracellular domain of the receptor.

Figure 3. Representation of hormone specificity and physiological and pathophysiological function(s) of GC-A/NPRA

After ligand-binding, GC-A/NPRA is shown to generate second messenger cGMP from the hydrolysis of GTP. An increased level of intracellular cGMP stimulates and activates three known cGMP effecter molecules namely; cGMP-dependent protein kinases (PKGs), cGMP-dependent phosphodiesterases (PDEs), and cGMP-dependent ion-gated channels (CNGs). The cGMP-dependent signaling may antagonize a number of pathways including; intracellular Ca²⁺ release, IP₃ formation, activation of protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs), and production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (Il-6). The resulting cascade can mimic ANP/NPRA/cGMP-dependent responses in both physiological and pathophysiological environments. The activation of NPRC may lead to a decrease in cAMP levels and an increase in IP₃ production. The extracellular ligand binding domain (LBD), transmembrane region (TM), and intracellular protein kinase-like homology domain (KHD) and guanylyl cyclase catalytic domain (GCD) of GC-A/NPRA are shown. DD, represents the dimerization domain of NPRA. The ligand binding domain, transmembrane region, and small intracellular tail of NPRC are also indicated.