Conformations and States

Activation of G-protein coupled receptors by agonists is thought to involve the stabilisation of a ternary complex of agonist/receptor/G-protein, leading to effector activation, but this mechanism may be an oversimplification, as follows: (a) Agonist binding to the free receptor (uncoupled from G-proteins) is not a neutral event, but includes a component of the activation process and may be described in terms of the stabilisation of a partly activated form of the receptor (R*) that is able to couple to the G-protein. Stabilisation of R*, therefore, may contribute to agonist efficacy. Also, determinations of agonist affinity even in the absence of G-protein coupling do not necessarily describe the affinities of agonists for the ground state of the receptor. (b) R* is a partly activated intermediate between the ground state of the receptor (R) and the activated form coupled to G-protein (R*G). There is some indication that different agonists may stabilise different conformational states of the receptor, i.e. different R* species. (c) Agonists also stabilise the activated, coupled form of the receptor (AR*G), and for some agonists acting at a single receptor, the activated states may be similar, although there is evidence for other agonists that different activated states with different activities may be stabilised. (d) Two or more efficacy-generating steps are involved in the activation of G-protein coupled receptors by agonists: the stabilisation of R*, the stabilisation of R*G, and possibly the modulation of the activity of the activated state (AR*G). (e) The experimentally observed excess of G-proteins over receptors in membranes is inconsistent with data obtained from ligand-binding assays on these receptors. Receptors and G-proteins, therefore, may exist in some form of higher order array with cooperative interactions. BIOCHEM PHARMACOL 58;7:1081–1088, 1999. © 1999 Elsevier Science Inc.