Abstract
Different ligands for G protein‐coupled receptors can induce unique receptor conformations, leading to differing profiles of G protein coupling. Given that S. cerevisiae expression systems are useful tools for studying the coupling of GPCRs to individual G protein pathways, experiments were undertaken to investigate whether different pharmacological profiles can be detected in this system for ligands of the adenosine A1 receptor (A1R), and to what extent the findings correlated to a mammalian (CHO) expression system. The human A1R was introduced into individual strains of S. cerevisiae, each expressing different chimeras from yeast and mammalian Gα subunits, followed by pharmacological characterisation. We found that, in the yeast, the A1R only couples to Gαi/o family proteins when stimulated with the full agonist, R‐PIA. The pA2 values generated from analysis of the interaction between the A1R antagonist, DPCPX, and R‐PIA correlated with that observed in mammalian cell assays. A novel partial agonist at the A1R, VCP‐189, was also tested. VCP‐189 appeared to selectively activate Gαi subtypes, but no response was seen with Gαo or Gαz strains. In agreement with the S. cerevisiae assay, the response to R‐PIA and VCP‐189 in the mammalian assays is pertussis toxin sensitive. Further studies investigating Gαi/o subtype selectivity in mammalian cells are currently underway.
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