Lysophosphatidic acid inhibits C-type natriuretic peptide activation of guanylyl cyclase-B.
C-type natriuretic peptide (CNP), found in endothelial cells, chondrocytes, and neurons, binds its cognate transmembrane receptor, natriuretic peptide receptor-B (NPR-B/GC-B), and stimulates the synthesis of the intracellular signaling molecule, cGMP. The known physiologic consequences of this binding event are vasorelaxation, inhibition of cell proliferation, and the stimulation of long bone growth. Here we report that 10% fetal bovine serum markedly reduced CNP-dependent cGMP elevations in NIH3T3 fibroblast. The purified serum components platelet-derived growth factor and lysophosphatidic acid (LPA) mimicked the effect of serum on CNP-dependent cGMP elevations, but the latter factor resulted in the most dramatic reductions. The LPA-dependent inhibition was rapid and dose dependent, having t(1/2) and IC(50) values of approximately 5 min and 3.0 micro M LPA, respectively. The decreased cGMP concentrations resulted from reduced CNP-dependent NPR-B guanylyl cyclase activity that did not require losses in receptor protein or activation of protein kinase C, indicating a previously undescribed desensitization pathway. These data suggest that NPR-B is repressed by LPA and that one mechanism by which LPA exerts its effects is through the heterologous desensitization of the CNP/NPR-B/cGMP pathway. We hypothesize that cross-talk between the LPA and CNP signaling pathway maximizes the response of fibroblasts in the wound-healing process.
Abbey
Sarah E
SE
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Potter
Lincoln R
LR
D016475:3T3 Cells; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D015153:Blotting, Western; D006152:Cyclic GMP / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D000099242:Atrial Natriuretic Factor Receptor B
D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP; D006162:Guanylate Cyclase; D008246:Lysophospholipids; D020098:Natriuretic Peptide, C-Type; D010982:Platelet-Derived Growth Factor; D017461:Receptors, Atrial Natriuretic Factor; D013755:Tetradecanoylphorbol Acetate; D000099242:Atrial Natriuretic Factor Receptor B; C091715:atrial natriuretic factor receptor A