Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 456

activity is low, but that reduce constitutive receptor activity by binding pref-
erentially to R and pulling the equilibrium toward the “off” state. Implicit in
two-state models, however, is the assumption that ligand binding affects
only the proportion of receptors in the “active” state, not the nature of that
state. If the receptor is the sole determinant of activity, then ligand classifi-
cation must be independent of the assay used to detect R * , that is, the rel-
ative order of potency for a series of ligands cannot vary when two or more
assays of receptor activation are employed.
The situation becomes much more complex if one allows for the exis-
tence of more than one active receptor conformation. 6-8 Since there is no
a priori reason to assume that a conformation that enables coupling to one
downstream effector will necessarily couple it to all possible downstream
effectors, one must consider the possibility of multiple R * conformations
that differ in their signaling capacity. Further, if receptors can adopt more
than one R * conformation, there is no a priori reason to assume that chem-
ically distinct ligands will generate an identical distribution of active states or
even that the ligand-induced active state will mimic the spontaneously
formed active state. As increasingly diverse assays for measuring receptor
activity were introduced, it became clear that the relative activity of agonists
does not always adhere to the predictions of simple receptor theory, that is,
structurally distinct ligands can stabilize different conformational
populations and elicit ligand-specific efficacy signatures. 2,9 The first formal
model to account for these digressions postulated that it is the lig-
and-receptor complex, not the receptor alone, that specifies the active
state. 6 Whether through conformational selection, that is, choosing from
a menu of spontaneously formed R * states, or conformational induction,
that is, forcing novel R * conformations, each ligand-receptor combination
has the potential to “bias” the coupling of the receptor to different signaling
pathways.
Figure 18.1 A illustrates the differences between conventional full and
partial agonism and biased agonism using a hypothetical GPCR with five
conformationally distinct “active” states (R * 1-R * 5), each of which couples
the receptor to downstream G protein and non-G protein effectors with
different efficiency. Note that the 1:1 coupling between “active” state
and effector depicted is an oversimplification. In such a system, a full agonist
(A) will bind and stabilize R * 1-R * 5 equivalently and shift 100% of
the receptor population into an “active” state at full receptor occupancy (rel-
ative intrinsic efficacy ¼ 1). Although there are exceptions, 21 native hor-
mones and neurotransmitters are most commonly full agonists, as they