The expression of mammalian G protein coupled receptors (GPCRs) in S. cerevisiae provides a powerful assay system for functional analysis, ligand identi®cation and pharmaceutical screening. However, relatively few receptors have been coupled to the pheromone response pathway via the yeast G a , Gpa1p, or chimeric yeast/mammalian G a subunits containing long C-terminal regions of mammalian G a proteins. We tested an extended range of seven such chimeras for G a sub-types of three major classes (G ai/o , G as and G aq ), against eight human GPCRs (SST 2 , SST 5 , 5-HT 1A , 5-HT 1Da , ML 1B , P2Y 1 and P2Y 2 ). Although the G ai/o chimeras increased the range of receptors that coupled ef®ciently, the G as and G aq chimeras were inactive when expressed using the GPA1 promoter. We describe 10 novel Gpa1p chimeras, designated `transplants', in which the C-terminal ®ve amino acids of Gpa1p were exchanged with mammalian residues. Coupling ef®ciency and ligand sensitivity improved signi®cantly using the transplants. For the P2Y purinergic receptors, coupling could only be detected with the transplants; this is the ®rst report of G q speci®city coupling in yeast. Thus, the transplants offer major advantages over previously described approaches, in terms of both the range of receptors coupled and the ef®ciency of coupling.