Arrestins in Metabolic Regulation - Progress in Molecular Biology and Translational Science - page 409

which are located adjacent to b cells in the endocrine portion of the pan-
creas. Merlen et al. studied the functional relationship between glucagon
receptor endocytosis, phosphorylation, and coupling to the adenylate
cyclase pathway. 47 They found that following administration of a saturating
dose of glucagon to rats, a rapid internalization of glucagon receptor was
observed coincident with its serine phosphorylation both at the plasma
membrane and within endosomes. Coincident with glucagon receptor
endocytosis, a massive internalization of both the 45- and 47-kDa Gs a pro-
teins were also observed. In contrast, no change in the subcellular distribu-
tion of adenylate cyclase or b -arrestin-1 and -2 were observed. Krilov et al.
found that the glucagon receptor recycles through Rab4- and Rab11-
positive vesicles. The actin cytoskeleton, b -arrestin-1, b -arrestin-2, and
the receptor's carboxyl terminus are involved in recycling. 48
Both insulin and endothelin type A (ETA) can stimulate the activation of
ETA receptor, leading to G q/11 protein and PI3K activation, subsequently
promoting glucose transport by enhancing the translocation of GLUT4, the
predominant glucose transporter in skeletal muscle, and white and brown
adipocytes. 49 b -Arrestin-1 promoted ETA-stimulated, but not insulin-
stimulated, GLUT4 translocation. b -Arrestin-1 associated with the ETA
receptor in an agonist-dependent manner and recruited Src kinase to the
ETA receptor thus forming a signal complex. 50 It was concluded that
b -arrestin-1 and Src kinase form a molecular complex with the ETA recep-
tor to mediate ETA signaling to G q/11 with subsequent stimulation of glu-
cose transport.
The pineal hormone melatonin is well known to affect carbohydrate
metabolism, but it also inhibits insulin secretion through the GPCRs
mT1 (also known as mTNr1A) and mT2 (also known as mTNr1B), which
are expressed in islets and clonal b -cells. 51 mT1 and mT2 signal through G i
proteins to inhibit adenylate cyclase and reduce cAMP. Bondi et al. used
coimmunoprecipitation analysis and found that in the presence of melato-
nin, b -arrestin-2 is required for the formation of MT1 receptor/G
protein/MEK1/2/ERK1/2 complexes. 52 b -Arrestin-2 mediates the
endocytosis of mT1 receptor and forms b -arrestin-2/MEK1/2/ERK1/2
complexes upon the activation of mT1.
3.4. Peroxisome proliferator-activated receptors
Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear
receptor proteins that function as master transcription factors to regulate gene