Biology Reference
In-Depth Information
A
Partial agonist
Full agonist
Biased agonist
Intrinsic efficacy
(R*1; R*2; R*3; R*4; R*5 = 0.2)
Intrinsic efficacy
(R*1; R*2; R*3; R*4; R*5 = 1)
Intrinsic efficacy
(R*1; R*2; R*3 = 0.0; R*4; R*5 = 1)
A
B
C
R*1
R*2
R*3
R*4
R*5
GRK
GRK
G
s
G
q/11
G
12/13
Arr2
Arr3
G
α
G
α
G
α
g
g
g
Arr
Arr
b
b
b
Uncoupl
ing
AC
PLC
β
Rho-GEF
Cofilin
Src
Raf
MEK
ERK
PP2A
AKT
PKA
PKC
Rho
Chronofin
GSK3
LIMK
“Tightly coupled” or
amplified responses
“Weakly coupled” or
threshold responses
“Stoichiometric” or non-amplified responses
G protein
signaling network
Arrestin
signaling network
Figure 18.1 Agonism, partial agonism, and “bias” in GPCR signaling. (A) Schematic
depicting a hypothetical GPCR with five conformationally distinct “active” states
(R*1-R*5), each of which couples the receptor to downstream G protein (G
s
;G
q/11
;
G
12/13
) and non-G protein [arrestin2 (Arr2); arrestin3 (Arr3) effectors] with different effi-
ciency. In such a system, a conventional full agonist (A) will produce a full system
response in all downstream effectors. Due to a lower intrinsic efficacy, a partial agonist
(B) may produce a full system response in tightly coupled or highly amplified systems,
yet exhibit reduced or absent efficacy toward effectors that are weakly coupled, have
high activation thresholds, or are non-amplified. Nevertheless, differences between full
and partial agonist signaling reflect the efficiency with which they stabilize receptors in
the “active” state (intrinsic efficacy), not their ability to distinguish between different
active states. In contrast, “biased” agonists (C) engage different active receptor confor-
mations with variable intrinsic efficacy, a property that permits them to activate some
downstream pathways, for example, arrestin-dependent signals, while antagonizing
others. The therapeutic potential of “biased” agonism lies in this ability to qualitatively
change GPCR signaling.
(Continued)
Search WWH ::
Custom Search