Ldtrsprotean Agonism

LDTRS is the concept that different ligands can direct intracellular signaling to particular pathways. It was first introduced by Berg et al. (1998) who showed that the 5 -HT2C receptor can couple to two different pathways in Chinese hamster ovary cells (inositol phosphate accumulation and arachidonic acid release) and exhibit a markedly different rank order of efficacies for each response (Fig. 2.2b) [17] . It has been proposed that LDTRS may result from the ability of receptors to spontaneously adopt a variety of different conformations and that a particular ligand can stabilize a certain conformational species to produce a particular biological response [18]. Some insight into how the pharmacology of a particular ligand-receptor interaction can be altered by the nature of the transducing protein (e.g., heterotrimeric G protein alpha subunit) with which the ligand-receptor complex interacts can, however, also be gained from a consideration of allosteric interactions (see also Section 2.4 below). For all intents and purposes, the binding site on the receptor at which the receptor--G protein interaction occurs can be considered to be an allosteric binding site, with the G protein alpha subunit acting as the allosteric regulator via this site (Fig. 2.1c). As a consequence, the binding of the receptor to a particular G protein alpha subunit can change the way in which a particular exogenous ligand can interact with the receptor's orthosteric binding site (at which the endogenous agonist normally interacts).

The potential for ligand-directed trafficking is further complicated by the increasing evidence that GPCRs can elicit downstream signaling responses that are mediated independently of heterotrimeric G proteins -19-21] . For example, it is becoming clear that P-arrestin may have an important role in orchestrating both the location of receptors within particular signaling domains of a cell and their ability to trigger a range of different responses, including the activation of the p42/44 MAP kinase pathway [22-25] . These G protein--ndependent mechanisms are not limited to those involving P-arrestin, and evidence has accumulated for a role for other signaling and scaffolding proteins, including caveolin-1, A-kinase anchoring proteins, and the Na/K exchange protein [26-29].

Receptor-mediated events within the cell are therefore complex, and there is the possibility that a given receptor can evoke multiple effects via a combination of G protein and non-G protein-mediated events within the same cell. This complexity is nicely illustrated by the human P2- adrenoceptor, which can signal through both cyclic adenosine monophosphate (AMP) accumulation and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation [22, 23, 30]. At this receptor, the prototypical P-blocker propranolol can act as an inverse agonist on Gs-mediated cyclic AMP accumulation, but as an agonist of P-arrestin-mediated ERK1/2 phosphorylation (Fig. 2.2c,d) [22,23]. Furthermore, evidence is now accumulating to suggest that antagonist affinities may also vary depending upon the agonist and signaling response used to screen for them [30].

The concept that certain agonists can reverse their effects under different physiological situations was suggested by Kenakin (2001) in his discussion of protean agonism [31] . His hypothesis was that some agonists (protean agonists) may produce an active receptor conformation that has a lower efficacy than the spontaneously active conformation (in the absence of agonist) that is responsible for constitutive receptor activity. As a consequence, in a consti-tutively active system where there is a significant proportion of spontaneously active receptors, activation by a protean agonist would lead to a ligand-receptor conformation that has lower efficacy than the constitutively active (agonist-free) receptor conformation. In this situation, the protean agonist would manifest itself as inverse agonist. In a quiescent system (i.e., no constitutive activity), the same ligand would produce an agonist effect by virtue of changing the predominant resting state of the receptor to the more active protean conformation. Thus, in a quiescent system, the protean ligand acts as an agonist and, in a constitutively active system, the ligand is an inverse agonist. Protean agonism has been suggested to explain the in vitro and in vivo actions of proxyfan at the histamine H3-receptor (which appears to be consti-tutively active under physiological conditions; Fig. 2.2d) [32].

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