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Antagonists of bradykinin that stabilize a G-protein-uncoupled state of the B2 receptor act as inverse agonists in rat myometrial cells

Leeb-Lundberg, L. M.Fredrik LU ; Mathis, Sandra A. and Herzig, Maryanne C.S. (1994) In Journal of Biological Chemistry 269(42). p.25970-25973
Abstract

Several B2 bradykinin (BK) receptor-specific antagonists including HOE140, NPC17731, and NPC567 exhibited negative intrinsic activity, which was observed as a decrease in basal phosphoinositide hydrolysis in primary cultures of rat myometrial cells, and this response was opposite to that elicited by the agonist BK. The order of potency of the antagonists in attenuating basal activity was essentially the same as that in competing both [3H]BK and [3H]NPC17731 for binding to B2 receptors on both intact rat myometrial cells and bovine myometrial membranes. We previously proposed a three-state model for the binding of agonists to G-protein-coupled B2 receptors in bovine myometrial membranes (Leeb-Lundberg, L. M. F. and... (More)

Several B2 bradykinin (BK) receptor-specific antagonists including HOE140, NPC17731, and NPC567 exhibited negative intrinsic activity, which was observed as a decrease in basal phosphoinositide hydrolysis in primary cultures of rat myometrial cells, and this response was opposite to that elicited by the agonist BK. The order of potency of the antagonists in attenuating basal activity was essentially the same as that in competing both [3H]BK and [3H]NPC17731 for binding to B2 receptors on both intact rat myometrial cells and bovine myometrial membranes. We previously proposed a three-state model for the binding of agonists to G-protein-coupled B2 receptors in bovine myometrial membranes (Leeb-Lundberg, L. M. F. and Mathis, S. A. (1990) J. Biol. Chem. 265, 9621-9627). This model was based on the ability of BK to promote the sequential formation of three receptor binding states where formation of the third, equilibrium state was blocked by Gpp(NH)p (guanyl-5'-yl imidodiphosphate) identifying it as the G-protein- coupled state of the receptor. Here, we show that, in contrast to BK, these antagonists bound preferentially to a G-protein-uncoupled state of the receptor. These results indicate that B2 receptor antagonists that stabilize a G-protein-uncoupled state of the receptor act as inverse agonists. Furthermore, these results provide strong evidence that endogenous G-protein- coupled receptors exhibit spontaneous activity in their natural environment in the absence of agonist occupancy.

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author
publishing date
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Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
269
issue
42
pages
25970 - 25973
publisher
ASBMB
external identifiers
  • scopus:0028113891
  • pmid:7929307
ISSN
0021-9258
language
English
LU publication?
no
id
9fdbe106-58f7-41ea-8dc9-7fa54ef47f6f
alternative location
http://www.jbc.org/content/269/42/25970.abstract
date added to LUP
2019-06-12 11:41:12
date last changed
2020-01-13 01:59:37
@article{9fdbe106-58f7-41ea-8dc9-7fa54ef47f6f,
  abstract     = {<p>Several B2 bradykinin (BK) receptor-specific antagonists including HOE140, NPC17731, and NPC567 exhibited negative intrinsic activity, which was observed as a decrease in basal phosphoinositide hydrolysis in primary cultures of rat myometrial cells, and this response was opposite to that elicited by the agonist BK. The order of potency of the antagonists in attenuating basal activity was essentially the same as that in competing both [<sup>3</sup>H]BK and [<sup>3</sup>H]NPC17731 for binding to B2 receptors on both intact rat myometrial cells and bovine myometrial membranes. We previously proposed a three-state model for the binding of agonists to G-protein-coupled B2 receptors in bovine myometrial membranes (Leeb-Lundberg, L. M. F. and Mathis, S. A. (1990) J. Biol. Chem. 265, 9621-9627). This model was based on the ability of BK to promote the sequential formation of three receptor binding states where formation of the third, equilibrium state was blocked by Gpp(NH)p (guanyl-5'-yl imidodiphosphate) identifying it as the G-protein- coupled state of the receptor. Here, we show that, in contrast to BK, these antagonists bound preferentially to a G-protein-uncoupled state of the receptor. These results indicate that B2 receptor antagonists that stabilize a G-protein-uncoupled state of the receptor act as inverse agonists. Furthermore, these results provide strong evidence that endogenous G-protein- coupled receptors exhibit spontaneous activity in their natural environment in the absence of agonist occupancy.</p>},
  author       = {Leeb-Lundberg, L. M.Fredrik and Mathis, Sandra A. and Herzig, Maryanne C.S.},
  issn         = {0021-9258},
  language     = {eng},
  month        = {10},
  number       = {42},
  pages        = {25970--25973},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Antagonists of bradykinin that stabilize a G-protein-uncoupled state of the B2 receptor act as inverse agonists in rat myometrial cells},
  url          = {http://www.jbc.org/content/269/42/25970.abstract},
  volume       = {269},
  year         = {1994},
}