D2 dopamine receptors are targeted by antipsychotic agents to regulate behavior. Likhite et al. found putative arginine methylation motifs in some human G protein–coupled receptors (GPCRs), including the D2 dopamine receptor, and in homologs in the worm Caenorhabditis elegans. Methylation of the D2 dopamine receptor by the arginine methyltransferase PRMT5 enhanced D2 receptor signaling in cultured cells. C. elegans lacking prmt-5had behavioral problems similar to those in worms deficient in the D2-like receptor DOP-3. Thus, methylation of GPCRs may be important for clinically relevant targets such as the D2 receptor.