FIGURE 1. Possible mechanisms of drug-induced changes in the sensitivity of a G_i-coupled receptor (for example, opioid, cannabinoid and certain dopamine receptors).

Drug-induced adaptations in the efficacy of receptor–G_i coupling could contribute to drug tolerance or sensitization. A possible mechanism is altered phosphorylation of the receptor by GRKs or its subsequent association with arrestins (1). Other possibilities include alterations in G-protein - (2) or -subunits (3) or in other proteins (for example, phosducin (4) or RGS proteins (5)) that modulate G protein function. Phosphorylation of the receptor by protein kinase A (6) or other kinases represents another potential mechanism. Also shown is agonist-induced receptor internalization, which may be mediated by receptor phosphorylation. From ref. 3.