Non-G Protein-Coupled Receptor (GPCR) Substrates for GPCR Kinases (GRKs)

G protein-coupled receptors are one of the most enormous and important receptor families found in nature. They are 7-transmembrane receptors coupled to G proteins and detect a wide range of stimuli such as light, odors, taste, ions, and peptides. The activated GPCR is desensitized via two mechanisms: heterologous vs homologous desensitization. In homologous desensitization a class of mammalian kinase is responsible for serine/threonine phosphorylation of agonist activated receptor, called GPCR kinases (GRKs). This class includes 7 kinases. It was first thought that GRKs could only phosphorylate ligand-activated GPCRs, but by discovering some of its non-GPCR targets we decide to collect data about them and the effects of their phosphorylation. By searching in pubmed database and studying a review article, we have found these non-GPCR substrates phosphorylated by GRKs: β-Arrestin 1, Dream, ENaCs, Nedd4 & Nedd4-2, Ezrin & Radixin, Tubulin, PDGFRβ, EGFR, NHERF, Hip, IRS-1, PDEγ, p38 MAPKs, Phosducin & PhLP, R-Smads, synucleins, ribosomal protein P2, HDAC, NPM1, P53, APC, LRP6, NFκB p105 & IκBα. We investigate about the phosphorylation sites of these targets, the effects of their phosphorylation by GRKs on cell signaling, and the cultures or cells whose phosphorylations have been reported. Finally we discuss that the GRKs' role in homologous desensitization of GPCRs are not sufficient to explain all of GRKs functions, so we propose new roles for GRKs in cell processes by phosphorylating these non-GPCR substrates. We also discuss about difficulties accompanied finding these targets and suggest more in vivo studies for them.