Figure 1.

Proposed model of a GPCR with multiple interconverting conformational and functional states. The model includes both ligand-receptor (green) and ligand-free receptor (blue) signaling. Each receptor state could exist in varying complexes and subcellular locations with distinct signaling cascades. Both neutral antagonists and inverse agonists can block R^O activation in competition with agonists, whereas only inverse agonists can non-competitively block the ligand-free states R^O*, R*, and R**. The extent to which acutely activated ligand-free R* accounts for overall signaling of an agonist depends on the rate constants k1, k2, and k3. The R** state is defined by altered ligand-free signaling after drug pretreatments and washout, or after physiological stimuli. The model has profound implications for potency and efficacy of agonists and antagonists, and it poses the hypothesis that ligands can accelerate interconversions between ligand-free signaling receptor states and the ground state R^O.