The G protein β subunit is a determinant in the coupling of Gs to the β1-adrenergic and A2a adenosine receptors

The signaling specificity of five purified G protein beta gamma dimers, beta (1)gamma (2), beta (2)gamma (2), beta (3)gamma (2), beta (4)gamma (2), and beta (5)gamma (2), was explored by reconstituting them with G(s) alpha and receptors or effecters in the adenylyl cyclase cascade. The ability of the five beta gamma dimers to support receptor-alpha-beta gamma interactions was examined using membranes expressing the beta (1)-adrenergic or A2a adenosine receptors, These receptors discriminated among the defined heterotrimers based solely on the beta isoform. The beta (4)gamma (2), dimer demonstrated the highest coupling efficiency to either receptor. The beta (5)gamma (2) dimer coupled poorly to each receptor, with EC50 values 40-200-fold higher than those observed with beta (4)gamma (2). Strikingly, whereas the EC50 of the beta (1)gamma (2), dimer at the beta (1)-adrenergic receptor was similar to beta (4)gamma (2), its EC50 was 20-fold higher at the A2a adenosine receptor. Inhibition of adenylyl cyclase type I (AC1) and stimulation of type II (AC2) by the beta gamma dimers were measured. beta gamma dimers containing G beta (1-4) were able to stimulate AC2 similarly, and beta (5)gamma (2) was much less potent. beta (1)gamma (2), beta (2)gamma (2), and beta (4)gamma (2) inhibited AC1 equally; beta (3)gamma (2), was 10-fold less effective, and beta (5)gamma (2), had no effect, These data argue that the beta isoform in the beta gamma dimer can determine the specificity of signaling at both receptors and effectors.