Enhanced calcium cycling and contractile function in transgenic hearts expressing constitutively active G alpha o* protein.

Published

Journal Article

In contrast to the other heterotrimeric GTP-binding proteins (G proteins) Gs and Gi, the functional role of G o is still poorly defined. To investigate the role of G alpha o in the heart, we generated transgenic mice with cardiac-specific expression of a constitutively active form of G alpha o1* (G alpha o*), the predominant G alpha o isoform in the heart. G alpha 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 alpha o* transgenic mice in vivo, along with increased L-type Ca2+ channel current density, calcium transients, and cell shortening in ventricular G alpha 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 alpha o* ventricles. Density and affinity of beta-adrenoceptors, cAMP levels, and PKA activity were comparable in G alpha o* and wild-type myocytes, but protein phosphatase 1 activity was reduced upon G alpha o* expression, particularly in the vicinity of the ryanodine receptor. We conclude that G alpha 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 alpha o activation.

Full Text

Duke Authors

Cited Authors

  • Zhu, M; Gach, AA; Liu, G; Xu, X; Lim, CC; Zhang, JX; Mao, L; Chuprun, K; Koch, WJ; Liao, R; Koren, G; Blaxall, BC; Mende, U

Published Date

  • March 2008

Published In

Volume / Issue

  • 294 / 3

Start / End Page

  • H1335 - H1347

PubMed ID

  • 18192223

Pubmed Central ID

  • 18192223

Electronic International Standard Serial Number (EISSN)

  • 1522-1539

International Standard Serial Number (ISSN)

  • 0363-6135

Digital Object Identifier (DOI)

  • 10.1152/ajpheart.00584.2007

Language

  • eng