G_i-1/G_i-2-dependent signaling by single-transmembrane natriuretic peptide clearance receptor

Abstract

Single-transmembrane natriuretic peptide clearance receptor (NPR-C), which is devoid of a cytoplasmic guanylyl cyclase domain, interacts with pertussis toxin (PTx)-sensitive G proteins to activate endothelial nitric oxide synthase (eNOS) expressed in gastrointestinal smooth muscle cells. We examined the ability of NPR-C to activate other effector enzymes in eNOS-deficient tenia coli smooth muscle cells; these cells expressed NPR-C and NPR-B but not NPR-A. Atrial natriuretic peptide (ANP), the selective NPR-C ligand cANP-(4-23), and vasoactive intestinal peptide (VIP) inhibited (125)I-ANP and (125)I-VIP binding to muscle membranes in a pattern indicating high-affinity binding to NPR-C. Interaction of VIP with NPR-C was confirmed by its ability to inhibit (125)I-ANP binding to membranes of NPR-C-transfected COS-1 cells. In tenia muscle cells, all ligands selectively activated G(i-1) and G(i-2); VIP also activated G(s) via VIP(2) receptors. All ligands stimulated phosphoinositide hydrolysis, which was inhibited by ANP-(1-11), PTx, and antibodies to phospholipase C-beta3 (PLC-beta3) and Gbeta. cANP-(4-23) contracted tenia muscle cells; contraction was blocked by U-73122 and PTx and by antibodies to PLC-beta3 and Gbeta in intact and permeabilized muscle cells, respectively. VIP and ANP contracted muscle cells only after inhibition of cAMP- and cGMP-dependent protein kinases. ANP and cANP-(4-23) inhibited forskolin-stimulated cAMP in a PTx-sensitive fashion. We conclude that NPR-C is coupled to activation of PLC-beta3 via betagamma-subunits of G(i-1) and G(i-2) and to inhibition of adenylyl cyclase via alpha-subunits.

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

“…80 It may participate in mediating some of the cellular actions of NPs via coupling to G i proteins and negative modulation of adenylyl cyclase activity. 81 However, within the cardiovascular system, the primary action of the NPR-C seems to be the modulation of circulating and local NP concentrations that are available to bind GC-A and GC-B. 82 Hence, changes in GC-A-mediated responses to ANP could theoretically result from changes in the expression levels of NPR-C.…”

The natriuretic peptide system in eels: a key endocrine system for euryhalinity?

“…Because NPR-C exhibits equally high affinity to all NPs, is distributed ubiquitously in various tissues in large amounts, and is internalized quickly after binding of ligands, NPR-C is believed to be a clearancetype receptor responsible for regulating plasma NP levels (54). However, recent data suggest that NPR-C is involved in the stimulation of nitric oxide production through G i proteins in gastrointestinal smooth muscle cells (62). At present, therefore, the NP system consists of at least three hormones and three receptors in mammals.…”

“…Furthermore, NPR-D is not distributed ubiquitously in various tissues, as is the case with NPR-C, but is localized mostly in the brain. Thus NPR-D may have some function in the brain and thus serves as a good model to pursue any new biological functions of the GCdeficient receptors (62). In other nonmammalian species, NPR-B has been isolated and characterized in the spiny dogfish, Squalus acanthias, which has only CNP as a ligand (1).…”

Cellular Effects of Guanylin and Uroguanylin

“…A third receptor that binds these three peptides, the so-called clearance receptor (or NPR-C), has no guanylate cyclase activity, and hormone binding to this receptor leads to endocytosis of the hormone-receptor complex and activation of a pertussis toxin-sensitive G-protein. The latter mediates an inhibition of adenylate cyclase (15,16). Guanylate cyclases D, E, and F (GC-D, GC-E, and GC-F) are expressed in sensory organs, and, until now, their agonists and functions are not known (17)(18)(19)(20).…”

“…ANP activates two different types of receptors (64); one is GC-A, and, like GC-C, its activation leads to the production of cGMP (65). The other receptor is the natriuretic peptide receptor type C, or clearance receptor (NPR-C), which is a pertussis toxin-sensitive G-protein-coupled receptor (15,16). It remains to be clarified whether the G-protein-coupled receptors for UGN and ANP are the same or similar.…”