Editors' ChoiceMEDICINE

Inverse Agonist to the Rescue

Science Signaling  24 Feb 2009:
Vol. 2, Issue 59, pp. ec76
DOI: 10.1126/scisignal.259ec76

Nguyen et al. report that basal amounts of signaling by empty β2-adrenergic receptors (β2-ARs) appear to be critical for the development of asthma in a mouse model. This supports the possibility that a particular form of pharmacological inhibitor of receptor signaling (known as an inverse agonist) could provide an effective therapeutic strategy for the disease. That’s a surprising conclusion, given that standard therapy for asthma includes use of β2-AR agonists, which act directly on smooth muscle in the airway to cause dilation and increased airflow. This therapy is not ideal, however, as long-term use of β2-AR agonists can actually increase mortality of asthma patients. The authors took a cue from studies in congestive heart failure where stimulation of β2-ARs has acutely beneficial effects but causes detrimental effects after long-term use. In the heart, although short-term actions of β2-AR antagonists decrease the output of a weak and failing heart, chronic administration of certain antagonists improves heart function in the long run and decreases mortality. Indeed, although inverse agonists, which inhibit β2-AR signaling, would seem unlikely to help in asthma (acting acutely to cause narrowing of the airway), long-term administration of such agents actually improved asthma symptoms in the mouse model. Unlike neutral antagonists, which block access of activating ligands to the receptor, inverse agonists act on the empty receptor to block any constitutive or spontaneous activity of the receptor to signal through the classical mechanisms of G protein–coupled receptors. However, they can also stimulate signaling through alternative mechanisms. Nguyen et al. therefore compared the effects of long-term administration of inverse agonist with genetic knockout of the β2-AR. Similar improvement in asthmatic symptoms was seen in both cases. Furthermore, a neutral antagonist (without inverse agonist properties) did not influence the development of asthma. Thus, the authors conclude that too much β2-adrenergic signaling, rather than too little, may be a determining factor in the debilitating effects of asthma. Penn provides commentary and considers the potential impact of the findings on therapeutic strategies in humans.

L. P. Nguyen, R. Lin, S. Parra, O. Omoluabi, N. A. Hanania, M. J. Tuvim, B. J. Knoll, B. F. Dickey, R. A. Bond, β2-Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model. Proc. Natl. Acad. Sci. U.S.A. 106, 2435–2440 (2009). [Abstract] [Full Text]

R. B. Penn, Agonizing over agonism: Should asthmatics turn their β-receptors on or off? Proc. Natl. Acad. Sci. U.S.A. 106, 2095–2096 (2009). [Full Text]