Galphaq reduces cAMP production by decreasing Galphas protein abundance

The heterotrimeric guanine nucleotide-binding protein Gαq transduces signals from heptahelical transmembrane receptors (e.g., α₁-adrenergic, endothelin 1A, and angiotensin II) to stimulate generation of inositol-1,4,5-trisphosphate and diacylglycerol. In addition, Gαq decreases cAMP production, through unknown mechanisms, and thus affects physiological responsiveness of cardiac myocytes and other cells. Here, we provide evidence that Gαq expression increases Gαs ubiquitination, decreases Gαs protein content, and impairs basal and β₁-adrenergic receptor-stimulated cAMP production. These biochemical and functional changes are associated with Akt activation. Expression of constitutively active Akt also decreases Gαs protein content and inhibits basal and β₁-adrenergic receptor-stimulated cAMP production. Akt knockdown inhibits Gαq-induced reduction of Gαs protein. In addition, MDM2, an E3 ubiquitin ligase, binds Gαs and promotes its degradation. Therefore, increased expression of Gαq decreases cAMP production through Akt-mediated Gαs protein ubiquitination and proteasomal degradation.