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“functional selectivity.”Whatever term is applied, the implications for signal
transduction are striking. To the extent that ligand binding can alter this
diverse array of protein interactions, functional selectivity has the potential
to modify GPCR signaling.
The concept of ligand-directed signaling raises the potential of pharma-
cologic agents with novel efficacy profiles possessing improved therapeutic
efficacy or reduced side effects. Functional selectivity has been described for
a number of GPCRs, including the PTH
1
R in bone,
15,37-45
the angiotensin
II type 1A receptor,
46
the
b
2-adrenergic receptor,
37
and the thyrotropin
receptor.
47
“Functional selectivity” can range from relatively modest devi-
ations in rank order of potency to frank reversal of efficacy, such that the
characterization of a ligand as agonist, antagonist or inverse agonist becomes
assay dependent. Put another way, conventional GPCR pharmacology
addresses changing the
quantity
of efficacy; that is, increasing or decreasing
receptor activity. In contrast, functional selectivity revolves around chang-
ing the
quality
of efficacy by amplifying desired signaling effects while
diminishing other unwanted effects. Thus, development of ligands with
novel GPCR stimulus trafficking characteristics is of significant pharmaco-
logic interest in relation to drug design.
48-52
To date, however, there is little
experimental evidence that biased ligands offer advantages over conven-
tional agonists/antagonists
in vivo
.
2.4. Arrestins as mediators of GPCR signaling
The arrestins, a family of four GPCR binding proteins that regulate recep-
tor desensitization and endocytosis, are among the most studied protein
modulators of GPCR signaling. Arrestins bind tightly and specifically to
agonist-occupied GPCRs that have been phosphorylated by GPCR
kinases
53
and sterically inhibit the receptor from further G protein activa-
tion. The two nonvisual arrestin isoforms,
b
-arrestins 1 and 2, also regulate
the agonist-induced internalization of desensitized GPCRs via clathrin-
coated pits.
54
The discovery that arrestins serve as adapters not only in the context of
GPCR sequestration but also in linking activated receptors to additional
effectors of downstream signaling
55
advanced our understanding of GPCR
signal transduction. It is now recognized that a number of catalytically active
proteins bind arrestins and are recruited to agonist-occupied GPCRs.
Among these are Src family tyrosine kinases; components of the ERK1/2
and c-Jun N-terminal kinase 3; mitogen-activated protein kinase
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