Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 464

The same story holds for the effects of conventional and arrestin
pathway-selective biased agonists on integrated biological responses such
as cell proliferation or migration. For example, both AngII and SII have been
reported to produce positive inotropic and lusitropic effects in isolated
murine cardiomyocytes that are arrestin dependent. 42 Likewise, the reported
ability of SII to stimulate proliferation of neonatal rat cardiomyocytes is a
property shared with AngII; its lack of a hypertrophic response reflects its
inability to activate G q/11 -dependent pathways, not its ability to engender
novel responses. 43 Similarly, the capacity to promote arrestin-dependent cell
survival and stimulate migration in primary murine osteoblasts is a property
shared by (D-Trp 12 ,Tyr 34 )-PTH(7-34) and hPTH(1-34). 44 Both the native
and biased ligands couple the receptor to arrestins and activate similar
arrestin-dependent biological responses.

3.2. Arrestin-selective ligand bias in vivo

If, as available in vitro data suggest, arrestin pathway-selective biased ligands
activate a subset of the signaling repertoire activated by a full agonist, then
the simple expectation would be that in vivo , these ligands would reproduce
part of the biological activity of the corresponding native hormone. Surpris-
ingly, the limited data available suggest this is not necessarily the case, and
that emergent biological properties may arise when arrestin-selective biased
agonists are used in vivo.
The actions of the arrestin pathway-selective PTH 1 R agonist, (D-Trp 12 ,
Tyr 34 )-bPTH(7-34), may be the most informative in this regard, in that its
in vivo effects at the genomic level have been characterized and correlatedwith
its phenotypic response (Refs. 31,44 ; see Chapter 13 ). Parametric geneset
enrichment analysis performed on cDNAmicroarray data fromcalvarial bone
of wild-type C57BL/6 mice treated with vehicle, the conventional PTH 1 R
agonist, hPTH(1-34), or (D-Trp 12 ,Tyr 34 )-bPTH(7-34), found a striking
degree of non-overlap in the genome level responses to the two ligands. 44
As expected of a conventional PTH 1 R agonist based on study of the actions
of native PTH in bone, 45-47 hPTH(1-34) affected gene clusters classically
associated with embryologic skeletal patterning and PTH actions in bone,
including Wnt/ b -catenin signaling, bone morphogenic protein signaling,

TGF- signaling, phosphatidylinositol 3-kinase (PI3K)/AKT signaling,

and ERK/MAPK signaling, 48,49 translating into regulation of processes
linked to the control of skeletal morphogenesis, osteoblast differentiation,
matrix biosynthesis, and mineralization, and bone turnover. In contrast,

b