The mechanism for the rapid desensitization in bradykinin-stimulated inositol monophosphate production in NG108-15 cells involves interaction of a single receptor with multiple signaling pathways.
We have previously shown that the mechanism for the rapid desensitization in bradykinin (BDK)-stimulated inositol monophosphate (IP) production in NG108-15 cells involves both a rapid loss of receptors from the cell surface and an uncoupling of the receptor:G-protein:phospholipase C (PLC) signaling process, with protein kinase C (PKC) activation playing a role only at a postreceptor level (Wolsing and Rosenbaum, 1991). In contrast to BDK, a 5-min pretreatment with the BDK receptor "antagonist" NPC-567 is sufficient to cause a substantial decrease in the subsequent BDK maximal response (Emax) without altering either the BDK potency (EC50) or the BDK receptor number. An 18-hr pretreatment of the cells with 200 ng/ml pertussis toxin (PT) does not alter the BDK response (Fold stim = 2.36 +/- 0.18 vs. 2.00 +/- 0.25 in controls, N = 4), reiterating previous observations that BDK-stimulated IP production in this cell line is mediated by a pertussis toxin (PT)-insensitive G-protein. However, PT pretreatment significantly (P < .05) attenuates the receptor loss that accompanies the desensitization process. Taken together, these data imply that the BDK receptor in NG108-15 cells interacts with both PT-sensitive and PT-insensitive G-proteins. Because NPC-567 pretreatment results in a desensitization that is not accompanied by receptor loss, it appears that NPC-567 is able to facilitate an agonistic interaction with only the PT-insensitive G-proteins that are available to the receptor.
Procter & Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio.
D H
DH
Wolsing
J S
JS
Rosenbaum
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000502:physiology; D005910:Glioma / Q000378:metabolism; D007295:Inositol Phosphates / Q000096:biosynthesis*; D009447:Neuroblastoma / Q000378:metabolism; D037342:Pertussis Toxin; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology*; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007295:Inositol Phosphates; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; D010566:Virulence Factors, Bordetella; C047872:inositol 2-monophosphate; C053010:NPC 567; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D001920:Bradykinin