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Vol. 56, Issue 2, 348-358, August 1999
2-Adrenergic Receptor/Gs Interactions:
Evidence for Multiple Receptor Conformations
Howard Hughes Medical Institute (R.S., U.K., K.W.-S., B.K.K.) and
Division of Cardiovascular Medicine (B.K.K.), Stanford University
Medical School, Stanford, California
The aim of our study was to examine the effects of different purine
nucleotides [GTP, ITP, and xanthosine 5'-triphosphate (XTP)] on
receptor/G protein coupling. As a model system, we used a fusion
protein of the 
2-adrenergic receptor and the 
subunit of the G protein Gs. GTP was more potent and efficient than
ITP and XTP at inhibiting ternary complex formation and supporting adenylyl cyclase (AC) activation. We also studied the effects of
several 2-adrenergic receptor ligands on nucleotide
hydrolysis and on AC activity in the presence of GTP, ITP, and XTP. The
efficacy of agonists at promoting GTP hydrolysis correlated well with
the efficacy of agonists for stimulating AC in the presence of GTP. This was, however, not the case for ITP hydrolysis and AC activity in
the presence of ITP. The efficacy of ligands at stimulating AC in the
presence of XTP differed considerably from the efficacies of ligands in
the presence of GTP and ITP, and there was no evidence for
receptor-regulated XTP hydrolysis. Our findings support the concept of
multiple ligand-specific receptor conformations and demonstrate the
usefulness of purine nucleotides as tools to study conformational
states of receptors.
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