The heterotrimeric guanine nucleotide-binding protein G alpha q transduces signals from heptahelical transmembrane receptors (e.g., alpha(1)-adrenergic, endothelin 1A, and angiotensin II) to stimulate generation of inositol-1,4,5-trisphosphate and diacylglycerol. In addition, G alpha q decreases cAMP production, through unknown mechanisms, and thus affects physiological responsiveness of cardiac myocytes and other cells. Here, we provide evidence that G alpha q expression increases G alpha s ubiquitination, decreases G alpha s protein content, and impairs basal and beta(1)-adrenergic receptor-stimulated cAMP production. These biochemical and functional changes are associated with Akt activation. Expression of constitutively active Akt also decreases G alpha s protein content and inhibits basal and beta(1)-adrenergic receptor-stimulated cAMP production. Akt knockdown inhibits G alpha q-induced reduction of G alpha s protein. In addition, MDM2, an E3 ubiquitin ligase, binds G alpha s and promotes its degradation. Therefore, increased expression of G alpha q decreases cAMP production through Akt-mediated G alpha s protein ubiquitination and proteasomal degradation. (C) 2008 Elsevier Inc. Alt rights reserved.