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G protein-coupled receptor 147 was expressed in mouse islets and alpha TC1 clone 6 cells.RFRP-3 promoted survival of alpha TC1 clone 6 cells under hyperglycemia and serum starvation.RFRP-3 activated PI3K/AKT and ERK1/2 pathways.GPR147 antagonist RF9 blocked the activation of both PI3K/AKT and ERK1/2.RFRP-3 increased the expression of proliferating cell nuclear antigen (PCNA).Type 2 diabetes mellitus (T2DM) is closely related to islet alpha cell mass and viability. Several types of RFamide-related peptides (RFRPs) are involved in regulating proliferation and function of islet cells. However, current understanding of the role of RFamide-related peptide-3 (RFRP-3) in pancreatic alpha cells is limited. Therefore, we investigated the expression of the RFRP-3 receptor, G protein-coupled receptor 147 (GPR147), in mouse islets and alpha TC1 clone 6 cells, and evaluated the function of RFRP-3 on alpha cells. We show that GPR147 is expressed in mouse islets and alpha cell lines. In addition, RFRP-3 promotes survival of alpha cells under conditions of hyperglycemia and serum starvation. Mechanistic evidence demonstrates that RFRP-3 activated PI3K/AKT and ERK1/2 signaling cascades and treatment with an antagonist of GPR147, 1-adamantanecarbonyl-Arg-Phe-NH2 (RF9) blocked this function. These findings indicate a novel effect of RFRP-3 in promoting alpha cell survival, likely via GPR147.