Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of beta-arrestins

作者：Bouzo Lorenzo Monica; Santo Zas Icia; Lodeiro Maria; Nogueiras Ruben; Casanueva Felipe F; Castro Marian; Pazos Yolanda; Tobin Andrew B; Butcher Adrian J^*; Camina Jesus P^*

来源：Scientific Reports, 2016, 6(1): 22495.

DOI：10.1038/srep22495

The growth hormone secretagogue receptor, GHSR1a, mediates the biological activities of ghrelin, which includes the secretion of growth hormone, as well as the stimulation of appetite, food intake and maintenance of energy homeostasis. Mapping phosphorylation sites on GHSR1a and knowledge of how these sites control specific functional consequences unlocks new strategies for the development of therapeutic agents targeting individual functions. Herein, we have identified the phosphorylation of different sets of sites within GHSR1a which engender distinct functionality of beta-arrestins. More specifically, the Ser(362), Ser(363) and Thr(366) residues at the carboxyl-terminal tail were primarily responsible for beta-arrestin 1 and 2 binding, internalization and beta-arrestin-mediated proliferation and adipogenesis. The Thr(350) and Ser(349) are not necessary for beta-arrestin recruitment, but are involved in the stabilization of the GHSR1a-beta-arrestin complex in a manner that determines the ultimate cellular consequences of beta-arrestin signaling. We further demonstrated that the mitogenic and adipogenic effect of ghrelin were mainly dependent on the beta-arrestin bound to the phosphorylated GHSR1a. In contrast, the ghrelin function on GH secretion was entirely mediated by G protein signaling. Our data is consistent with the hypothesis that the phosphorylation pattern on the C terminus of GHSR1a determines the signaling and physiological output.

• 出版日期2016-3-3