Models

The models in this chapter are based on the assumption that receptors can only adopt an inactive (R) and an active (R*) conformation in the absence of G proteins and that only the latter is capable of G protein coupling. One view is to consider that agonists are necessary for receptor activation and that it is only the active agonist-receptor (AR*) complex that induces G protein activation (Figures 171 and 172). This model is, in fact, derived from Koshland's famous 'induced fit model' (Koshland et al., 1966). For such coupling to take place, the bound agonist is obviously supposed to induce a conformational change in the receptor.

'Ligand induction' predicts that transition from the inactive (R) to the active (R*) state is extremely rare in the absence of agonist because of the energy barriers between R and R*. The free energy of agonist binding to R is used to overcome the energy barrier and facilitates (or induces) the transition to R*. If the process of receptor activation is explicitly stipulated, the collision coupling model (Tolkovsky and Levitzki, 1978) can be represented by Figure 171.

Figure 171 Agonist-induced transition from the inactive (R) to the active (R*) receptor state is followed by G protein coupling to the active agonist-receptor complex (AR*).

Ligand Induction

Ligand Induction

Figure 172 Ligand induction model for noradrenaline-induced p2-adrenergic receptor activation (Gether and Kobilka, 1998, reproduced by permission of the American Society for Biochemistry and Molecular Biology).

Figure 172 Ligand induction model for noradrenaline-induced p2-adrenergic receptor activation (Gether and Kobilka, 1998, reproduced by permission of the American Society for Biochemistry and Molecular Biology).

The second equilibrium (defined by equilibrium constant L) forms the key element for discriminating between agonists and antagonists:

• For antagonists, the second equilibrium is completely shifted to the left; all of the occupied receptors remain in the inactive conformation.

• For agonists, the second equilibrium is shifted more to the right for strong agonists as for weak agonists, so that more of the occupied receptors reside in the active conformation.

The concept of agonist-induced receptor conformation has been the subject of many debates, especially since the discovery of constitutive GPCR activity in recombinant receptor systems. In this respect, spontaneous receptor-G protein complex formation can be demonstrated by, for example:

• Co-immunoprecipitation of receptors and G proteins under basal conditions.

• The fact that basal levels of cellular activity in many systems is directly dependent on the receptor density.

A situation in where receptors acquire the active conformation and couple to G proteins even in the absence of ligands can be described by an alternative 'conformational selection model' (Figures 173 and 174), which is derived from the 'plausible model' (Monod et al, 1965). In this model, the active and inactive receptor conformations (i.e. R* and R) are in equilibrium, even in the absence of lig-and and the agonist 'favours' a conformational change of the receptor because of its a + r + g

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