Insights into the molecular mechanisms of partial agonism

A compelling question that also arises when discussing conformational changes involved in GPCR activation is the molecular mechanism underlying partial agonism, that is, the fact that some compounds elicit physiological responses lower than that of a so-called full agonist. According to the classical two-state model ofreceptor activation the physiological response is determined by the ability of a given ligand to alter the distribution between the inactive state (R) and the active state (R*) (Samama et al. 1993). While a full agonist would be predicted to move the majority of the receptor molecules into the R* state, a partial agonist would cause a less dramatic change in the distribution between R and R* (Samama et al. 1993). Accordingly, a lower fraction of receptor molecules would reside in R* as compared to what is seen in response to the full agonist and as a result the physiological response will be smaller. However, increasing evidence indicates that the action of partial agonists cannot be explained sufficiently within the framework of such a two-state model (see Gether 2000). Recent analysis of fusion proteins between GaS and the wild-type p2 adrenergic receptor and between GaS and a constitutively activated p2 adrenergic receptor mutant have, for example, showed an interesting discrepancy between the efficacy of ligands in stimulating GTPase activity and in their ability to stabilize the ternary complex, that is, high affinity, GTP sensitive agonist binding (Seifert etal. 2001). The data suggest the possibility that partial agonism at least in some cases maybe explained by the ability of certain partial agonist to strongly stabilize the ternary complex resulting in a reduced rate of G protein turnover as compared to the full agonist (Seifert et al. 2001). Further support for a complex action of partial agonists has been obtained in recent biophysical studies. These studies include both the application of single-molecule fluorescence analysis as well as fluorescence lifetime analysis to a purified preparation of the p2 adrenergic receptor covalently labelled with a fluorescence reporter molecule (Ghanouni et al. 2001a; Peleg et al. 2001). The data demonstrated clear evidence for the existence of different conformational sub-states of the p2 adrenergic receptor that are differentially modulated by different agonists thus suggesting that different agonists stabilizes distinct conformational states of the receptor molecule (Ghanouni et al. 2001a; Peleg et al. 2001).

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