Arrestins in Bone - Progress in Molecular Biology and Translational Science - page 334

and b -arrestin 2 KO mice suggests that b -arrestin 2 targets prominently p38
MAPK- and NF k B-dependent signaling pathways in osteoblasts exposed to
intermittent PTH. 86

3.4. Biased agonism at the PTH receptor
The PTH 1 R has long served as a model for the study of biased agonism.
Through the generation of numerous PTH peptide analogs, it has been
demonstrated that the downstream signaling events induced by the PTH 1 R
are sensitive to alterations in ligand structure. Examples of pathway-selective
PTH 1 R agonists are highlighted in Table 13.1 . The closest mimetic of intact
PTH(1-84), PTH(1-34) acts as a conventional/full agonist with respect to
PTH 1 R signaling, activating G s and G q/11 signaling and promoting
b -arrestin-dependent receptor desensitization and internalization.
In addition, PTH(1-34) stimulates b -arrestin-dependent downstream sig-
naling. Shorter N-terminal fragments of the PTH peptide, for example,
PTH(1-31) and [Aib1,3,M]PTH(1-15), preferentially promote G s
coupling, 88-90 while N-terminal truncations, for example, PTH(3-34), pro-
mote G q/11 coupling while failing to activate G s. 89,91,92 Trp 1 -PTHrp(1-36)
has been shown to activate ERK1/2 exclusively through a G s /PKA-

Table 13.1 Reported efficacy profiles of the conventional agonist, PTH(1 - 34), and
selected biased PTH 1 R agonists

G Protein
coupling

Ligand

b -Arrestin coupling

References

PTH(1-34) G s and

G q/11

-Arrestin 1 and 63,69-72

b

-arrestin 2

b

[Aib 1,3 ,M]PTH(1-15)

G s only ND 43

PTH(1-31) G s only ND 44,45

PTH(3-34) G q only ND 40-42

PTH(28-42) G q only ND 41,42

PTH(28-48) G q only ND 41,42

Trp 1 -PTHrp(1-36) G s only Antagonist 63

Bpa 1 -PTHrp(1-36) G s only Antagonist 38,39

D -Trp 12 ,Tyr 34 -bPTH
(7-34)

Inverse G s
agonist

-Arrestin 1 and 15,63,87

b

-arrestin 2

b

ND, not determined.