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J Biol Chem, Vol. 274, Issue 42, 29603-29606, October 15, 1999
From the Department of Biochemistry, The University of Texas
Health Science Center, San Antonio, Texas 78284-7760
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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