title: Sphingosine-1-phosphate inhibits C-type natriuretic peptide activation of guanylyl cyclase B (GC-B/NPR-B).
abstract: C-type natriuretic peptide (CNP) binds and activates the transmembrane guanylyl cyclase B receptor (NPR-B), which decreases vascular tone and inhibits cell proliferation and migration. In contrast, the bioactive lipid sphingosine-1-phosphate (S1P) elicits the opposite physiological effects. Here, we demonstrate a potent acute inhibitory effect of S1P on NPR-B activity in NIH3T3 fibroblasts and A10 vascular smooth muscle cells. In fibroblasts, S1P reduced CNP-dependent cGMP elevations to the same levels as 10% fetal bovine serum, the most potent NPR-B desensitizing agent known. The reduction was dose-dependent (IC50=0.08 micromol/L) and due to decreased NPR-B activity because CNP-dependent guanylyl cyclase activities were markedly diminished in membranes prepared from S1P-treated cells. Similarly, in A10 cells, S1P inhibition was rapid (t1/2=2 to 5 minutes), dose-dependent (IC50=0.3 micromol/L S1P), and mediated by a cell surface receptor. The mechanism of the S1P-dependent desensitization in A10 cells did not require NPR-B degradation or protein kinase C activation, but did require elevated calcium concentrations because a nonspecific calcium ionophore also inhibited NPR-B and an intracellular calcium chelator blocked a significant portion of the S1P response. These are the first data demonstrating cross-talk between the natriuretic peptide and S1P signaling systems. They suggest that the effects of S1P on vascular disease and wound healing may be mediated in part through inhibition of NPR-B.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Abbey-Hosch
authors.forename: Alyssa N
authors.initials: AN
authors.lastname: Cody
authors.forename: Lincoln R
authors.initials: LR
authors.lastname: Potter
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015759:Ionomycin / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D041681:NIH 3T3 Cells / Q000187:drug effects / Q000201:enzymology; D020098:Natriuretic Peptide, C-Type / Q000008:administration & dosage / Q000494:pharmacology*; D009928:Organ Specificity; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011956:Receptors, Cell Surface; C414616:guanyl cyclase-B receptor; D020098:Natriuretic Peptide, C-Type; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C060504:dihydrosphingosine 1-phosphate; D004533:Egtazic Acid; D015759:Ionomycin; D006162:Guanylate Cyclase; D006152:Cyclic GMP; C070515:bisindolylmaleimide I; D013110:Sphingosine