Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 328

is believed to have evolved from a common ancestor. While retaining their
heptahelical structure and their functional coupling to heterotrimeric
G proteins, this class of receptors has evolved into subfamilies characterized
by distinct structural elements and diverse modes of ligand binding, receptor
activation, and receptor regulation. 18,19 This evolutionary diversity trans-
lates into the capacity for GPCRs to detect an enormous array of extracel-
lular stimuli. GPCR signaling is fundamental to numerous biologic
functions including vision, taste, and odorant sensory detection, neurotrans-
mission, endocrine control of physiological homeostasis and reproduction,
and regulation of hemodynamics and intermediary metabolism. As a
result, agents targeting GPCR signaling have been a principal focus of phar-
maceutical development, and it is estimated that almost half of all drugs in
clinical use target this ubiquitous family of receptors. 18,19
Earlier models of GPCR signaling envisioned the receptor existing in
equilibrium between two states: an inactive state (R) and an active state
(R * ) which is stabilized by agonist binding. 20-22 This allosteric model
viewed agonist binding as triggering conformational receptor changes that
coupled it to its associated G proteins, thereby regulating the activity of
enzymatic effectors, such as adenylate cyclases, phospholipase C b isoforms,
and ion channels, leading to the generation of small molecule “second mes-
sengers” that altered the physiological function of the cell. In these models,
the intrinsic efficacy of a ligand was simply seen as a reflection of its ability to
alter the R-R * equilibrium. Agonists stabilized the R * conformation,
pulling the equilibrium toward the “on” state, whereas “neutral” antagonists
bound indiscriminately to both R and R * , producing no physiological
response but blocking the response to agonists. The eventual discovery of
constitutively activating GPCRmutations allowed the detection of receptor
activity in the absence of ligand and enabled the identification of an addi-
tional class of ligands, termed inverse agonists , that suppressed basal receptor
activity. 23-25 Thus, inverse agonists appear as antagonists when basal recep-
tor activity is low but have the added property of reducing constitutive
receptor activity by binding preferentially to R and pulling the equilibrium
toward the “off” state.
With the development of increasingly sophisticated biochemical and
biophysical approaches for measuring ligand-receptor interactions, evidence
emerged that GPCRs assumemultiple “active” conformations that are capable
of interacting with intracellular effectors with varying efficiency. 22 Moreover,
these conformations can interact with ligands in a highly selective manner,
meaning that structurally distinct ligands may elicit unique ligand-specific