Arrestins Come of Age: A Personal Historical Perspective - Progress in Molecular Biology and Translational Science - page 9

This of course is in contrast to the classical simple 2-state model of receptor
signaling A þ R ⇆ AR * where R and R * are unitary inactive and active
states of the receptor, respectively, and A is an agonist. Despite a number
of recent biophysical studies suggesting such a multiplicity of receptor active
states, 56-58 their existence remains to be firmly established.
The existence of G protein or b -arrestin-biased ligands has now been
demonstrated for dozens of receptors. 59 In most cases, the “biased” ligands
are synthetic molecules. However, in at least one case, the CCR7 receptor,
one endogenous chemokine ligand, CCL21, is G-biased, whereas its other
endogenous ligand CCL19 is unbiased. 60 Other examples will likely be
forthcoming. At least one case of an endogenously expressed, entirely
b -arrestin-biased chemokine receptor, CXCR7, has been described. 61
The existence of such biased ligands has potential therapeutic implica-
tions. This is true because biased signaling allows for the possibility of design-
ing drugs with greater specificity and fewer side effects. The details of course
depend upon which effects of a receptor are desired ones, which are con-
sidered side effects, and which are mediated by b -arrestins versus G proteins.
Two quick examples will illustrate the point. Angiotensin receptor
blockers (ARBs) are widely used in clinical medicine because they block
the potentially deleterious G protein (G q )-mediated effects of the angioten-
sin II type 1A receptor to increase blood pressure via vasoconstriction. How-
ever, they also block potentially advantageous b -arrestin-mediated effects of
the receptor. These include increased cardiac performance and anti-
apoptosis. 62,63 A b -arrestin-biased angiotensin analog has been shown to
slow the progression of heart failure in animal models and might be useful
for the treatment of congestive heart failure. 64 Such a biased agonist of
course is itself a competitive antagonist of G protein-mediated signaling
(hence, it lowers blood pressure like a standard ARB) while simultaneously
activating b -mediated signaling (unlike standard ARBs). 65
A situation where a G-biased ligand might be therapeutically desirable is
the m -opioid receptor that mediates the pain relieving or antinociceptive
effects of opiate analgesics. These effects have been shown to be G i medi-
ated. However, prominent narcotic side effects such as tolerance, constipa-
tion, and respiratory depression seem to be mediated largely through
b -arrestin-mediated signaling. 66,67 Thus, one might speculate that a
G-biased m -opioid ligand would have preserved antinociceptive efficacy
with markedly reduced b -arrestin-dependent side effects. The potential
for such biased ligands to provide added therapeutic benefit is very attractive
but remains to be clinically demonstrated.