Heterologous desensitization of platelet-derived growth factor-mediated arachidonic acid release and prostaglandin synthesis.
Prolonged treatment of quiescent Swiss 3T3 cells with vasopressin induced heterologous desensitization of specific early signals stimulated by platelet-derived growth factor (PDGF). PDGF caused a striking dose-dependent release of [3H]arachidonic acid (EC50 = 2 ng/ml) and prostaglandin E2 (EC50 = 5 ng/ml). These responses are severely attenuated (greater than 85%) by prior exposure to vasopressin in a dose-dependent manner (IC50 = 1.5 nM). Maximal loss of responsiveness occurred after 40 h of vasopressin treatment with a half-maximal desensitization after 11-13 h. The desensitization is dependent upon binding to the V1 receptor, since it can be prevented by the antagonist [Pmp1,O-Me-Tyr2,Arg8]vasopressin. In contrast, stimulation of inositol phosphate accumulation and production of diacylglycerol and phosphatidic acid by PDGF are unchanged. Thus, the observed heterologous desensitization cannot be attributed to an inability to activate phospholipase C. Furthermore, prior exposure to vasopressin did not affect the ability of PDGF to evoke tyrosine phosphorylation of cellular substrates, demonstrating that vasopressin-induced heterologous desensitization causes a block at a point distal to activation of receptor tyrosine kinase activity. Other downstream responses including transient induction of c-fos expression and stimulation of DNA synthesis were attenuated by vasopressin pretreatment. The findings demonstrate a novel mechanism of heterologous cellular desensitization namely, persistent occupancy of a guanine nucleotide-binding protein-coupled receptor, like the V1 type vasopressin receptor, attenuates responsiveness to a polypeptide growth factor like PDGF that initiates responses through a tyrosine kinase receptor.
Domin
J
J
Imperial Cancer Research Fund, Lincoln's Inn Fields, London, United Kingdom.
Rozengurt
E
E
D016475:3T3 Cells; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004075:Diglycerides / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis*; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D010712:Phosphatidic Acids / Q000096:biosynthesis; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014667:Vasopressins / Q000494:pharmacology
D004075:Diglycerides; D007295:Inositol Phosphates; D010712:Phosphatidic Acids; D010982:Platelet-Derived Growth Factor; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014667:Vasopressins; D016718:Arachidonic Acid; D004247:DNA; D015232:Dinoprostone; D013936:Thymidine