Heterologous expression of many G-protein coupled receptors (GPCRs) is a major bottleneck in drug discovery efforts for therapeutic development of the receptor. The goal of this study was to utilize domains from a well-trafficked GPCR to aid in improving the trafficking of a related receptor. The adenosine A(2a) receptor (A(2a)R) shows exceptional expression and trafficking to the plasma membrane in yeast; however, this is not the case for other adenosine receptors. A(2a)R has a longer C-terminus than the other adenosine receptors, which may contribute to its exceptional trafficking to the plasma membrane. To test the possibility to improve trafficking of the adenosine A(1) receptor (A(1)R), chimeric receptors containing the seven transmembrane domains of A(1)R and the full-length or truncated A(2a)R C-terminus were constructed. The chimeric receptor showed improved localization to the plasma membrane and was capable of binding radioligand with native A(1)R affinity. Functionally active A(1)R receptor variants were produced at a theoretical yield of 95 pmol/mg total membrane protein, estimated using radioligand binding data, which are greater than three-fold higher than previously reported yields from other heterologous expression systems, and should facilitate biophysical characterization and drug discovery efforts. (c) 2018 American Institute of Chemical Engineers