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PYY, glucose-dependent insulinotropic polypeptide (GIP), CCK, and others.
Besides the enteroendocrine hormones, adipocytes secrete leptin as a signal
of total body fat mass.
b
-Arrestins actively participate in the signaling of
these orexigenic and anorexigenic peptides.
Ghrelin is an acylated 28 amino acid peptide secreted by the stomach just
before an expected meal, and strongly promotes food intake. Ghrelin is the
endogenous ligand for the growth hormone (GH) secretagogue-receptor
(GHS-R). Ghrelin inhibits insulin release in mice, rats, and humans. Low
plasma ghrelin levels are associated with elevated fasting insulin levels and
insulin resistance in humans. Cami˜a
et al.
found that besides the Ca(
2
þ
)-
dependent PKC/Src and phosphoinositide 3-kinase (PI3K)/PKC/Src path-
ways, the ghrelin receptor GHS-R1a also activates ERK1/2 via
b
-arrestin-
mediated pathways.
22
Binding of
b
-arrestin-1 and -2 to the receptor leads to
the formation of a multiprotein complex containing the
b
-arrestins, Src,
Raf-1, and ERK 1/2, indicating that
b
-arrestins act as scaffolding proteins
and signal transducers for GHS-R-activated ERK1/2 signaling. Damian
et al.
showed that ghrelin binding induces a specific GHS-R1a conforma-
tional change leading to agonist-dependent
b
-arrestin-2 recruitment to
the isolated GHS-R in lipid discs, whereas the interaction of GHS-R with
m
-AP2 is independent of ghrelin.
23
The distinct ligand requirements for the
interaction of the purified GHS-R1a with
b
-arrestin or AP2 provide a new
mechanism for the differential regulation of basal- and agonist-induced
receptor internalization in cells.
3. FUNCTIONAL ROLE OF
b
-ARRESTINS IN REGULATION
OF CARBOHYDRATE AND LIPID HOMEOSTASIS
Glucose metabolism in the liver (glycolysis and gluconeogenesis) is
regulated by insulin and glucagon via several transcription factors responding
to cAMP concentrations (cAMP-responsive element binding proteins;
CREBs). Key regulators of glucose metabolism include the forkhead tran-
scription factor, FOXO1, a CREB-regulated transcription coactivator 2,
GCN5 acetyltransferase, and ATF4.
3.1. Insulin signaling
The insulin signaling pathway is pivotal in maintaining metabolic homeo-
stasis. Of most importance, glucose homeostasis is maintained by the fine
orchestration of insulin secretion and insulin action to promote glucose
transport
into muscle and adipocytes. Normally,
the insulin receptor
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