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Spontaneous human B2 bradykinin receptor activity determines the action of partial agonists as agonists or inverse agonists. Effect of basal desensitization

Fathy, Dana B. ; Leeb, Tosso ; Mathis, Sandra A. and Leeb-Lundberg, L. M Fredrik LU (1999) In Journal of Biological Chemistry 274(42). p.29603-29606
Abstract

In this report, we show that desensitization regulates ligand- independent, spontaneous activity of the human B2 bradykinin (BK) receptor, and the level of spontaneous receptor activity determines the action of the BK antagonists and partial receptor agonists NPC17731 and HOE140 as agonists or inverse agonists. Spontaneous receptor activity was monitored by measuring basal cellular phosphoinositide (PI) hydrolysis as a function of the density of the receptor in transiently transfected HEK293 cells. Minimal spontaneous activity of the wild-type B2 receptor was detected in these cells. Mutating a cluster of serines and threonines within the fourth intracellular domain of the receptor, which is critical for agonist-promoted... (More)

In this report, we show that desensitization regulates ligand- independent, spontaneous activity of the human B2 bradykinin (BK) receptor, and the level of spontaneous receptor activity determines the action of the BK antagonists and partial receptor agonists NPC17731 and HOE140 as agonists or inverse agonists. Spontaneous receptor activity was monitored by measuring basal cellular phosphoinositide (PI) hydrolysis as a function of the density of the receptor in transiently transfected HEK293 cells. Minimal spontaneous activity of the wild-type B2 receptor was detected in these cells. Mutating a cluster of serines and threonines within the fourth intracellular domain of the receptor, which is critical for agonist-promoted desensitization, significantly increased the spontaneous receptor activity. BK, the natural B2 receptor ligand and, consequently, a full agonist, stimulated PI hydrolysis at high and low levels of spontaneous receptor activity. On the other hand, the partial agonists NPC17731 and HOE140 were stimulatory, or agonists, at the lower level of receptor activity but inhibitory, or inverse agonists, at the higher level of activity. These results show that receptors are desensitized in response to their spontaneous activity. Furthermore, these results, which refute traditional theories, show that the capacity of a drug to modulate a receptor response is not intrinsic to the drug but is also dependent on the cellular environment in which the drug acts.

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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
274
issue
42
pages
29603 - 29606
publisher
ASBMB
external identifiers
  • scopus:0033569746
  • pmid:10514427
ISSN
0021-9258
DOI
10.1074/jbc.274.42.29603
language
English
LU publication?
no
id
bbce8a8b-241e-443b-86ec-7e7384761c17
date added to LUP
2019-06-10 11:05:21
date last changed
2020-01-13 01:58:54
@article{bbce8a8b-241e-443b-86ec-7e7384761c17,
  abstract     = {<p>In this report, we show that desensitization regulates ligand- independent, spontaneous activity of the human B2 bradykinin (BK) receptor, and the level of spontaneous receptor activity determines the action of the BK antagonists and partial receptor agonists NPC17731 and HOE140 as agonists or inverse agonists. Spontaneous receptor activity was monitored by measuring basal cellular phosphoinositide (PI) hydrolysis as a function of the density of the receptor in transiently transfected HEK293 cells. Minimal spontaneous activity of the wild-type B2 receptor was detected in these cells. Mutating a cluster of serines and threonines within the fourth intracellular domain of the receptor, which is critical for agonist-promoted desensitization, significantly increased the spontaneous receptor activity. BK, the natural B2 receptor ligand and, consequently, a full agonist, stimulated PI hydrolysis at high and low levels of spontaneous receptor activity. On the other hand, the partial agonists NPC17731 and HOE140 were stimulatory, or agonists, at the lower level of receptor activity but inhibitory, or inverse agonists, at the higher level of activity. These results show that receptors are desensitized in response to their spontaneous activity. Furthermore, these results, which refute traditional theories, show that the capacity of a drug to modulate a receptor response is not intrinsic to the drug but is also dependent on the cellular environment in which the drug acts.</p>},
  author       = {Fathy, Dana B. and Leeb, Tosso and Mathis, Sandra A. and Leeb-Lundberg, L. M Fredrik},
  issn         = {0021-9258},
  language     = {eng},
  month        = {10},
  number       = {42},
  pages        = {29603--29606},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Spontaneous human B2 bradykinin receptor activity determines the action of partial agonists as agonists or inverse agonists. Effect of basal desensitization},
  url          = {http://dx.doi.org/10.1074/jbc.274.42.29603},
  doi          = {10.1074/jbc.274.42.29603},
  volume       = {274},
  year         = {1999},
}