Visualizing the Basis for Paracrine Natriuretic Peptide Signaling in Human Heart

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See related article, pages 183–190 Since the discovery of atrial natriuretic factor 25 years ago,1 there has been an explosion of research elucidating the basic biology of endogenous natriuretic peptides. Among other things, this work has established atrial natriuretic factor as one of a family of structurally similar endogenous natriuretic peptides with complex and distinct functional roles in maintaining normal homeostasis and responding to pathological circumstances. The first identified member of this family, atrial natriuretic peptide (ANP), is synthesized and secreted in the cardiac atria under normal conditions and by the ventricular myocardium during fetal development, hypertrophy, or heart failure. BNP, a distinct natriuretic peptide first isolated from the porcine brain, is preferentially synthesized and secreted by ventricular cardiac myocytes and, like ANP, exhibits increased expression during hypertrophy and heart failure. In contrast, C-type natriuretic peptide (CNP) is mainly produced by vascular endothelial cells and neurons, whereas urodilatin is synthesized and secreted by renal cells. The last identified member of this peptide family is dendroaspis natriuretic peptide (DNP), which was first isolated from the venom of the Green Mamba snake.2 Although immunoreactivity to DNP has been identified in several human tissues3 and circulating plasma,4 the gene encoding this natriuretic peptide has not yet been identified within the human genome. Actions of natriuretic peptides are mediated through binding to 3 distinct natriuretic peptide receptors (NPRs) that are located on the cell surface and bind endogenous ligands with varying specificities and affinities (Figure).5 Two of the receptors, NPR-A and NPR-B, have an extracellular (ligand-binding) domain linked to an intracellular (catalytic) domain with guanylate cyclase activity. Consequently, binding to NPR-A and NPR-B triggers increases in guanylate cyclase activity, increased intracellular cGMP, and downstream signaling and responses. The third natriuretic peptide receptor, NPR-C, has no catalytic domain …