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o PROTEIN
1 Medicine/Cardiology, Rhode Island Hospital, Providence, Rhode Island, United States; Medicine/Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, United States
2 Medicine/Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, United States
3 Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
4 Medicine, Duke University Medical Center, Durham, North Carolina, United States
5 Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
6 Medicine, University of Rochester, Rochester, New York, United States
* To whom correspondence should be addressed. E-mail: Ulrike_Mende{at}brown.edu.
In contrast to other heterotrimeric GTP-binding proteins (G proteins) Gs and Gi, the functional role of Go is still poorly defined. To investigate the role of G
o in the heart, we generated transgenic mice with cardiac-specific expression of a constitutively active form of Go1 (Go1* ), the predominant Go isoform in the heart. Go expression was increased 3- to 15-fold in mice from five independent lines, all of which had a normal life span and no gross cardiac morphological abnormalities. We demonstrate enhanced contractile function in Go* transgenic mice in vivo, along with increased L-type Ca2+ channel current density, calcium transients and cell shortening in ventricular Go*-expressing myocytes compared with wild-type controls. These changes were evident at baseline conditions and maintained after isoproterenol stimulation. Expression levels of all major Ca2+ handling proteins were largely unchanged, except for a modest reduction in the Na+/Ca2+ exchanger in transgenic ventricles. In contrast, phosphorylation of the ryanodine receptor (RyR2) and phospholamban at known protein kinase A (PKA) sites was increased 1.6- and 2-fold, respectively, in Go* ventricles. Density and affinity of 
-adrenoceptors, cAMP levels and PKA activity were all comparable in Go* and wild-type myocytes, but PP1 phosphatase activity was reduced upon Go* expression, particularly in the vicinity of RyR2. We conclude that Go* exerts a positive effect on Ca2+ cycling and contractile function. Alterations in PP1 activity rather than PKA-mediated phosphorylation appear might be involved in hyperphosphorylation of key Ca2+ handling proteins in hearts with constitutive Go activation.
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