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messenger-degrading enzymes (see Chapter 3 ). Hence, G protein-selective
“biased” agonists have potential as non-desensitizing ligands. Arrestin3 null
mice demonstrate prolonged opiate analgesia, 59,60 and a recently reported
G protein-biased mu opioid receptor agonist, TRV130, appears to mimic
the effects of arrestin3 knockout, producing potent analgesia with reduced
gastrointestinal dysfunction and respiratory depression than morphine in rats
and mice. 61 Another example is, the niacin receptor, GPR109A, which has
been shown to decrease serum free fatty acids by activating G i/o while at the
same time producing cutaneous flushing through arrestin-dependent activa-
tion of phospholipase A 2. 62 Predictably, a G protein pathway-selective
GPR109A agonist, MK-0354, has been shown to decrease serum free fatty
acids in vivo without causing flushing, making it a potentially useful agent for
treating hyperlipidemia. 63
4.2. Cell proliferation
Arrestins interface with several pathways that regulate progression of the cell
cycle (see Chapters 5 and 15 ). In some settings, arrestin-Src complexes
mediate the ability of GPCRs to transactivate the epidermal growth factor
(EGF) receptor tyrosine kinase pathway, stimulating EGF receptor-
dependent ERK1/2 activity and cell proliferation. 64 Arrestin2-Src also
increases cell proliferation by activating an Rb-Raf-1 pathway that pro-
motes Rb dissociation from E2F-responsive proliferative promoters, leading
to increased E2F1 binding, transcription of S-phase genes, and cell cycle
progression. 65 Conversely, direct scaffolding of the ERK1/2 cascade by
arrestins promotes cytosolic retention of active ERK1/2 and inhibits
GPCR-induced transcription and cell proliferation. 66-68
Whether arrestin-dependent signaling promotes or inhibits cell cycle
progression appears to vary between systems, perhaps depending on which
signaling pathway dominates. Primary calvarial preosteoblasts from arrestin3
null mice proliferate much faster that wild preosteoblasts, and the arrestin-
selective biased agonist (D-Trp 12 ,Tyr 34 )-bPTH(7-34) slows preosteoblast
proliferation in an arrestin3-dependent manner, suggesting that arrestins
restrain cell proliferation. 44 Conversely, neointimal hyperplasia following
carotid endothelial injury is diminished in arrestin3 null mice. Loss of
arrestin3 is associated with decreased GPCR-stimulated vascular smooth
muscle cell proliferation, ERK1/2 activation, and migration, consistent
with a role for arrestin3-signaling in mediating the proliferative response. 64
In this system, knockout of arrestin2 has the opposite effect, suggesting that
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