Sphingosine-1-Phosphate Inhibits C-Type Natriuretic Peptide Activation of Guanylyl Cyclase B (GC-B/NPR-B)

Sarah E. Abbey-Hosch, Alyssa N. Cody, Lincoln R. Potter

Research output: Contribution to journalArticle

28 Scopus citations

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 (SIP) elicits the opposite physiological effects. Here, we demonstrate a potent acute inhibitory effect of SIP on NPR-B activity in NIH3T3 fibroblasts and A10 vascular smooth muscle cells. In fibroblasts, SIP 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 μmol/L and due to decreased NPR-B activity because CNP-dependent guanylyl cyclase activities were markedly diminished in membranes prepared from SIP-treated cells. Similarly, in A10 cells, S1P inhibition was rapid (t1/2=2 to 5 minutes), dose-dependent (IC50=0.3 μmol/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.

Original languageEnglish (US)
Pages (from-to)1103-1109
Number of pages7
JournalHypertension
Volume43
Issue number5
DOIs
StatePublished - May 2004

Keywords

  • Atrial natriuretic factor
  • Cyclic GMP
  • Natriuretic peptides
  • Receptors
  • Vascular diseases

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