Arrestins in Metabolic Regulation - Progress in Molecular Biology and Translational Science - page 408

spatiotemporally separated signaling pathways. 37 PACAP alone induces
transient ERK1/2 activation via PAC1R through PKA- and Src-dependent,
but b -arrestin-1-independent pathways, and promotes the nuclear trans-
location of a fraction of phosphorylated ERK1/2 (p-ERK1/2). 38 In
contrast, in the presence of glucose, PACAP potentiates the glucose induced
long-lasting ERK1/2 activation via a b -arrestin-1-dependent pathway.
In addition, activation of ERK1/2 through the b -arrestin-1-dependent
pathway is involved in PACAP-induced IRS-2 protein expression, which
is crucial for b -cell function and survival.
The islets express two families of purinergic GPCRs, the P1 receptors
(activated by adenosine) and P2 receptors (activated by ATP and ADP).
The P2 receptor P2Y is expressed in islets. 39 Furthermore, there are six dif-
ferent P2Y receptor subtypes. Studies showed that in clonal b cells, P2Y1
and P2Y6 receptors are expressed in islets and are functionally active in stim-
ulating insulin secretion in a Ca 2 þ - and cAMP-dependent manner.
In contrast to P2Y, P1 receptor activation inhibits insulin secretion through
inhibition of adenylate cyclase activity. Hoffmann et al. found that the P2Y1
receptor binds b -arrestin-2 with higher affinity than b -arrestin-1. 40 Reiner
et al. analyzed the role of potential phosphorylation sites in the third intra-
cellular loop and the C-terminus of the human P2Y1 receptor for b -arrestin
binding and receptor internalization. 41 The mutation of potential phosphor-
ylation sites in the distal C-terminus of P2Y1 receptor fully prevented
b -arrestin-2 translocation, whereas truncation of the C-terminus adjacent
to the important sites (P2Y1-363) had no influence on internalization. 42
siRNA-mediated depletion of b -arrestin-1 almost completely attenuated
UTP-stimulated P2Y2-receptor desensitization, whereas knockdown of
b -arrestin-2 had no effect on P2Y2 signaling.
GIP is one of the major mediators in the regulation of nutrient-dependent
insulin release from the pancreas. 43,44 The GIP receptor is a member of the
class II GPCRs. 45 In bTC3 cells, expression of b -arrestin-1 attenuated
GIP-induced insulin release and cAMP production, whereas glucose-
stimulated insulin secretion was not affected. 46 These results suggest a poten-
tial role for b -arrestin-1 in modulating GIP-mediated insulin secretion in
pancreatic islet cells but the exact mechanism is not clear.
3.3. Glucagon and other GPCR signals
Glucagon is a hormone secreted by the pancreas that raises blood glucose
levels. Its effect is opposite to that of insulin, which lowers blood glucose
levels. Glucagon is synthesized and secreted from the a cells of the islets,