Interpretation of Efficacy for Receptors Acting through G-Proteins

6 Interpretation of Efficacy for Receptors Acting through G-Proteins 

Some of the most revealing studies of partial agonism (including Stephenson s seminal work) have been done with tissues in which G-proteins (see Chapters 2 and 7) provide the link between receptor activation and initiation of the response. In contrast to the situation with fast receptors with intrinsic ion channels (see above), it is not yet possible to observe the activity of individual G-protein-coupled receptors (with the potential exception of some that are linked to potassium channels) however, enough is known to show that the mechanisms are complex. The interpretation of differences in efficacy for agonists acting at such receptors is correspondingly less certain. 

An early model for the action of such receptors was as follows  

the agonist-receptor complex (AR) combines with a G-protein (G) to form a ternary complex (ARG ), which can initiate further cellular events, such as the activation of adenylate cyclase. However, this simple scheme (the ternary complex model) was not in keeping with what was already known about the importance of isomerization in receptor activation (see Sections 1.2.3 and 1.4.3), and it also failed to account for findings that were soon to come from studies of mutated receptors. In all current models of G-protein-coupled receptors, receptor activation by isomerization is assumed to occur so that the model becomes  

Complicated though these schemes might seem, they are in fact oversimplifications. Factors that have not been considered include  

---