Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active G[alpha]^sub o^ protein

In contrast to the other heterotrimeric GTP-binding proteins (G proteins) G... and G..., the functional role of G... is still poorly defined. To investigate the role of Gα... in the heart, we generated transgenic mice with cardiac-specific expression of a constitutively active form of Gα...* (Gα...*), the predominant Gα... isoform in the heart. Gα... 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...* transgenic mice in vivo, along with increased L-type Ca... channel current density, calcium transients, and cell shortening in ventricular Gα...*-expressing myocytes compared with wild-type controls. These changes were evident at baseline and maintained after isoproterenol stimulation. Expression levels of all major Ca... handling proteins were largely unchanged, except for a modest reduction in Na.../Ca... 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...* ventricles. Density and affinity of β-adrenoceptors, cAMP levels, and PKA activity were comparable in Gα...* and wild-type myocytes, but protein phosphatase 1 activity was reduced upon Gα...* expression, particularly in the vicinity of the ryanodine receptor. We conclude that Gα...* exerts a positive effect on Ca... cycling and contractile function. Alterations in protein phosphatase 1 activity rather than PKA-mediated phosphorylation might be involved in hyperphosphorylation of key Ca... handling proteins in hearts with constitutive Go activation. (ProQuest: ... denotes formulae/symbols omitted.)