Synucleins are a novel class of substrates for G protein-coupled receptor kinases

G protein-coupled receptor kinases (GRKs) specifically recognize and phosph orylate the agonist-occupied form of numerous G protein-coupled receptors ( GPCRs), ultimately resulting in desensitization of receptor signaling. Unti l recently, GPCRs were considered to be the only natural substrates for GRK s, However, the recent discovery that GRKs also phosphorylate tubulin raise d the possibility that additional GRK substrates exist and that the cellula r role of GRKs may be much broader than just GPCR regulation. Here we repor t that synucleins are a novel class of GRK substrates, Synucleins (alpha, b eta, gamma, and synoretin) are 14-kDa proteins that are highly expressed in brain but also found in numerous other tissues, alpha-Synuclein has been l inked to the development of Alzheimer's and Parkinson's diseases. We found that all synucleins are GRK substrates, with GRK2 preferentially phosphoryl ating the alpha and beta isoforms, whereas GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation of synuclein is activated by fact ors that stimulate receptor phosphorylation, such as lipids (all GRKs) and G beta gamma subunits (GRK2/3), suggesting that GPCR activation may regulat e synuclein phosphorylation, GRKs phosphorylate synucleins at a single seri ne residue within the C-terminal domain. Although the function of synuclein s remains largely unknown, recent studies have demonstrated that these prot eins can interact with phospholipids and are potent inhibitors of phospholi pase D2 (PLDS) in vitro, PLDS regulates the breakdown of phosphatidylcholin e and has been implicated in vesicular trafficking. We found that GRK-media ted phosphorylation inhibits synuclein's interaction with both phospholipid s and PLD2, These findings suggest that GPCRs may be able to indirectly sti mulate PLD2 activity via their ability to regulate GRK-promoted phosphoryla tion of synuclein.