New perspectives regarding β(2) -adrenoceptor ligands in the treatment of asthma

Abstract

In the last two decades several significant changes have been proposed in the receptor theory that describes how ligands can interact with G protein-coupled receptors (GPCRs). Here we briefly summarize the evolution of receptor theory and detail recent prominent advances. These include: (i) the existence of spontaneously active GPCRs that are capable of signalling even though they are unoccupied by any ligand; (ii) the discovery of ligands that can inactivate these spontaneously active receptors; (iii) the notion that a ligand may simultaneously activate more than one GPCR signalling pathway; and (iv) the notion that certain ligands may be able to preferentially direct receptor signalling to a specific pathway. Because the data supporting these receptor theory ideas are derived primarily from studies using artificial expression systems, the physiological relevance of these new paradigms remains in question. As a potential example of how these new perspectives in receptor theory relate to drug actions and clinical outcomes, we discuss their relevance to the recent controversy regarding the chronic use of β(2) -adrenoceptor agonists in the treatment of asthma.

Figure 1

Aside from the inactive conformation (R), all receptor conformations would be capable of constitutive activity according to their respective equilibrium constants. Straight solid, and dotted, arrows represent the equilibriums for ligands that are unbiased or perfectly biased, respectively. Curved arrows represent the spectrum of possible equilibriums for ligands that demonstrate imperfect bias.

Figure 2

Model of G protein-coupled receptor activation. Full agonists maximally stabilize receptors in an active conformation (R*), whereas full inverse agonists stabilize the inactive receptor conformation (R). Neutral antagonists, simply referred to as antagonists, have no effect on the R/R* equilibrium, but allow constitutive activity (CA) and block the effects of agonists and inverse agonists. Intrinsic activity is shown as −1, 0 and +1. Figure modified from Seifert and Wenzel-Seifert (Seifert and Wenzel-Seifert, 2002) and reproduced with permission of Naunyn–Schmiedeberg's Archives of Pharmacology.