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 b-adrenergic receptor kinase (bARKct) 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 bARK1, and a consecutive resensitization of b-adrenergic receptors (bAR), or rather due to inhibition of other Gbgmediated effects. In this study, we tested whether overexpression of N-terminally truncated phosducin (nt-delphosducin), another Gbg-binding protein that does not resensitize bARs owing to simultaneous inhibition of GDP release from Ga subunits, shows the same effects as bARKct. Adenoviral gene transfer was used to express ntdel-phosducin and bARKct in isolated ventricular cardiomyocytes and in myocardium of rabbits, which suffered from heart failure because of rapid ventricular pacing. bARstimulated cAMP formation was increased by bARKct, but not by nt-del-phosducin, whereas both proteins inhibited Gbg-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-delphosducin enhances the contractility of cardiomyocytes to the same extent as bARKct, suggesting that the effects of bARKct might be owing to inhibition of Gbg rather than to bAR resensitization.

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

“…Thus, the beneficial effects of βARKct could be also due to its inhibition of G bg signaling. In fact, Li et al (2003) have recently shown that, in rabbits with rapid ventricular pacing-induced heart failure, phosducin (a known G bg subunit-binding protein) exerted very similar beneficial effects on heart failure progression as did βARKct, but phosducin did not restore β-AR responsiveness as did βARKct. Thus, it is still an open question whether β-AR blocker-induced decrease in the (in CHF increased) activity of cardiac GRK2 can exert beneficial effects in the failing heart without affecting G bg signaling.…”

Cardiac Adrenoceptors: Physiological and Pathophysiological Relevance

“…Thus, it might be also possible that the beneficial effects of βARKct might be due to its inhibition of G βγ -signaling. In fact, Li et al (66) have recently shown that in rabbits with rapid ventricular pacinginduced heart failure, phosducin (a known G βγ -subunit binding protein) exerted very similar beneficial effects on heart failure progression as did βARKct, but phosducin did not restore βAR responsiveness as did βARKct. Thus, it is still an open question whether or not beneficial effects of βARKct in heart failure models are due to inhibition of GRK2 or to inhibition of G βγ -signaling.…”

Designing Heart Performance by Gene Transfer

“…More recently, gene transfer of the ␤ARK1ct has been compared with truncated phosducin, another GRK inhibitor (489). Both inhibitors bind to G␤␥ subunits, yet only ␤ARK-1 contributes to ␤-AR cycling and improves cAMP accumulation in myocytes from failing rabbit hearts (489).…”