Journal
CELLULAR SIGNALLING
Volume 50, Issue -, Pages 58-71Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2018.06.010
Keywords
G protein-coupled receptors; Neuropeptide Y receptors; Internalization; Arrestin; Supercomplex; Chimera
Categories
Funding
- German Science Foundation [SFB1052 TP A3]
- European Union (EU)
- federal state of Saxony
- European Regional Development Fund
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GPCR internalization, which is induced by arrestin recruitment, is an important mechanism for the regulation of signaling and receptor quantity at the cell surface. In this study, differences in the mechanism of arrestin-3 (arr-3) recruitment to the neuropeptide Y-1 and Y-2 receptor were identified. These receptors play an essential role in the regulation of feeding, energy homeostasis and cancer. The Y1R displays high affinity to arr-3, which induces rapid internalization of the arrestin/receptor complex. In contrast, the Y2R has a lower affinity for arr-3. Internalization is induced by arrestin binding, but arr-3 is released from the receptor and remains at the membrane while the receptor internalizes. Moreover, the deletion of the finger loop region of arr-3 reduces its agonist-dependent recruitment to the Y2R significantly, but not to the Y1R suggesting different binding conformations. For the first time, the formation of a supercomplex consisting of Y receptor, G alpha(0) protein and arrestin was studied by BRET-assay. We demonstrated that the Y1R is able to bind G alpha(0) protein as well as arr-3 simultaneously and internalizes as a supercomplex. For the Y2R no supercomplex formation was observed. By substituting the C-terminus or specific residues within the intracellular loop 1 and 2 of the receptors, the arr-3 recruitment of the Y1R and Y2R can be switched. Thus, we shed light on the specific spatio-temporal distribution of G alpha(0) protein and arrestin in response to Y-1 versus Y-2 receptor activation and identified the molecular determinants.
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