Inverse Agonists--Really Dual Efficacy Ligands?

Science's STKE  07 Oct 2003:
Vol. 2003, Issue 203, pp. tw386-TW386
DOI: 10.1126/stke.2003.203.tw386

Inverse agonists are defined by their ability to stabilize an inactive conformation of a receptor, which decreases signaling below basal levels. Azzi et al. show that β2-adrenergic receptor (β2AR) ligands are inverse agonists of G protein-mediated signaling, which decrease adenosine 3′,5′-monophosphate (cAMP), and they are partial agonists for stimulation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) mitogen-activated protein kinase (MAPK) cascade. ERK1/2 stimulation was independent of G protein subunits Gαi and Gαs but required the nonreceptor tyrosine kinase Src. Furthermore, experiments with dominant-negative fragments of β-arrestin or β-arrestin-deficient cells indicated that stimulation of ERK1/2 by these inverse agonists required β-arrestin, a protein involved in scaffolding and receptor desensitization. However, β-arrestin and β2AR complexes were extremely difficult to detect, which suggests a transient, low-affinity interaction. These results for the β2AR are especially important in light of the use of these inverse agonists in the treatment of hypertension and heart failure, which is also characterized by cardiac hypertrophy, a result of β-adrenergic receptor signaling. This partial agonist activity of inverse agonists was also observed for other G protein-coupled receptors, which suggests that inverse agonists may actually be dual-specificity ligands with the ability to stimulate (MAPK) or to inhibit specific (cAMP) downstream pathways.

M. Azzi, P. G. Charest, S. Angers, G. Rousseau, T. Kohout, M. Bouvier, G. Piñeyro, β-Arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc. Natl. Acad. Sci. U.S.A. 100, 11406-11411 (2003). [Abstract] [Full Text]