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
Dh. Wolsing et Js. Rosenbaum, 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, The Journal of pharmacology and experimental therapeutics, 266(1), 1993, pp. 253-261
We have previously shown that the mechanism for the rapid desensitizat
ion in bradykinin (BDK)-stimulated inositol monophosphate (IP) product
ion in NG108-15 cells involves both a rapid loss of receptors from the
cell surface and an uncoupling of the receptor:G-protein:phospholipas
e C (PLC) signaling process, with protein kinase C (PKC) activation pl
aying a role only at a postreceptor level (Wolsing and Rosenbaum, 1991
). In contrast to BDK, a 5-min pretreatment with the BDK receptor ''an
tagonist'' NPC-567 is sufficient to cause a substantial decrease in th
e subsequent BDK maximal response (E(max)) 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 BD
K response (Fold stim = 2.36 +/- 0.1 8 vs. 2.00 +/- 0.25 in controls,
N = 4), reiterating previous observations that BDK-stimulated IP produ
ction in this cell line is mediated by a pertussis toxin (PT)-insensit
ive G-protein. However, PT pretreatment significantly (P < .05) attenu
ates the receptor loss that accompanies the desensitization process. T
aken together, these data imply that the BDK receptor in NG108-15 cell
s interacts with both PT-sensitive and PT-insensitive G-proteins. Beca
use NPC-567 pretreatment results in a desensitization that is not acco
mpanied by receptor loss, it appears that NPC-567 is able to facilitat
e an agonistic interaction with only the PT-insensitive G-proteins tha
t are available to the receptor.