Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active Gα_o* protein

In contrast to the other heterotrimeric GTP-binding proteins (G proteins) G_s and G_i, the functional role of G_o is still poorly defined. To investigate the role of Gα_o in the heart, we generated transgenic mice with cardiac-specific expression of a constitutively active form of Gα_o1* (Gα_o*), the predominant Gα_o isoform in the heart. Gα_o expression was increased 3- to 15-fold in mice from 5 independent lines, all of which had a normal life span and no gross cardiac morphological abnormalities. We demonstrate enhanced contractile function in Gα_o* transgenic mice in vivo, along with increased L-type Ca²⁺ channel current density, calcium transients, and cell shortening in ventricular Gα_o*-expressing myocytes compared with wild-type controls. These changes were evident at baseline and maintained after isoproterenol stimulation. Expression levels of all major Ca²⁺ handling proteins were largely unchanged, except for a modest reduction in Na⁺/Ca²⁺ exchanger in transgenic ventricles. In contrast, phosphorylation of the ryanodine receptor and phospholamban at known PKA sites was increased 1.6- and 1.9-fold, respectively, in Gα_o* ventricles. Density and affinity of β-adrenoceptors, cAMP levels, and PKA activity were comparable in Gα_o* and wild-type myocytes, but protein phosphatase 1 activity was reduced upon Gα_o* expression, particularly in the vicinity of the ryanodine receptor. We conclude that Gα_o* exerts a positive effect on Ca²⁺ cycling and contractile function. Alterations in protein phosphatase 1 activity rather than PKA-mediated phosphorylation might be involved in hyperphosphorylation of key Ca²⁺ handling proteins in hearts with constitutive Gα_o activation.