Statins exert pleiotropic, cholesterol-independent effects by reducing isoprenylation of monomeric GTPases. Here we examined whether statins also reduce isoprenylation of γ-subunits of heterotrimeric G-proteins and thereby affect β-adrenergic signaling and regulation of force in cardiac myocytes. Neonatal rat cardiac myocytes (NRCM) were treated with atorvastatin (0.1–10 μmol/l; 12–48 h) and examined for adenylyl cyclase regulating G-protein α- (Gα), β- (Gβ), and γ- (Gγ) subunits and cAMP accumulation. Engineered heart tissue (EHT) from NRCM was used to evaluate contractile consequences. In atorvastatin-treated NRCM, a second band of Gγ3 with a lower apparent molecular weight appeared in cytosol and particulate fractions that was absent in vehicle-treated NRCM, but also seen after GGTI-298, a geranylgeranyl transferase inhibitor. In parallel, Gβ accumulated in the cytosol and total cellular content of Gαs was reduced. In atorvastatin-treated NRCM, the cAMP-increasing effect of isoprenaline was reduced. Likewise, the positive inotropic effect of isoprenaline was desensitized and reduced after treatment with atorvastatin. The effects of atorvastatin were abolished by mevalonate and/or geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate or squalene. Taken together, the results of this study show that atorvastatin desensitizes NRCM to β-adrenergic stimulation by a mechanism that involves reduced isoprenylation of Gγ and subsequent reductions in the cellular content of Gαs.

Key words: statins • receptor pharmacology • cardiac contractile function