期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 294, 期 3, 页码 H1335-H1347出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00584.2007
关键词
G proteins; signal transduction; calcium; contraction; transgenic mice
资金
- NHLBI NIH HHS [R01 HL072174, HL-072174] Funding Source: Medline
In contrast to the other heterotrimeric GTP-binding proteins ( G proteins) G(s) and G(i), the functional role of Go 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(o)1* (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.
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