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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/H1335    most recent 00584.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Zhu, M. Articles by Mende, U. Search for Related Content PubMed PubMed Citation Articles by Zhu, M. Articles by Mende, U.

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

¹Division of Cardiology, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, Rhode Island; ²Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ³Boston University School of Medicine, Boston, Massachusetts; ⁴Department of Medicine, Duke University Medical Center, Durham, North Carolina; ⁵Thomas Jefferson University, Philadelphia, Pennsylvania; and ⁶University of Rochester, Rochester, New York

Submitted 18 May 2007 ; accepted in final form 5 January 2008

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 G_o in the heart, we generated transgenic mice with cardiac-specific expression of a constitutively active form of G_o1* (G_o*), the predominant G_o isoform in the heart. G_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 G_o* transgenic mice in vivo, along with increased L-type Ca²⁺ channel current density, calcium transients, and cell shortening in ventricular G_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 G_o* ventricles. Density and affinity of β-adrenoceptors, cAMP levels, and PKA activity were comparable in G_o* and wild-type myocytes, but protein phosphatase 1 activity was reduced upon G_o* expression, particularly in the vicinity of the ryanodine receptor. We conclude that G_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 G_o activation.

G proteins; signal transduction; calcium; contraction; transgenic mice

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