Effects of two Gβγ-binding proteins - N-terminally truncated phosducin and β-adrenergic receptor kinase C terminus (βARKct) - In heart failure

Abstract

Myocardial overexpression of the C-terminus of β-adrenergic receptor kinase (βARKct) has been shown to result in a positive inotropic effect or an improvement of survival in heart failure. However, it is not clear whether this beneficial effect is mainly because of dominant-negative inhibition of βARK1, and a consecutive resensitization of β-adrenergic receptors (βAR), or rather due to inhibition of other Gβγ-mediated effects. In this study, we tested whether overexpression of N-terminally truncated phosducin (nt-del-phosducin), another Gβγ-binding protein that does not resensitize βARs owing to simultaneous inhibition of GDP release from Gα subunits, shows the same effects as βARKct. Adenoviral gene transfer was used to express nt-del-phosducin and βARKct in isolated ventricular cardiomyocytes and in myocardium of rabbits, which suffered from heart failure because of rapid ventricular pacing. βAR-stimulated cAMP formation was increased by βARKct, but not by nt-del-phosducin, whereas both proteins inhibited Gβγ-mediated effects. Both transgenes also increased contractility of normal and failing isolated cardiomyocytes and improved contractility in rabbits with heart failure after gene transfer in vivo. In conclusion, overexpression of nt-del-phosducin enhances the contractility of cardiomyocytes to the same extent as βARKct, suggesting that the effects of βARKct might be owing to inhibition of Gβγ rather than to βAR resensitization.