Opposite effects of Gαi2 or Gαi3 deficiency on reduced basal density and attenuated β-adrenergic response of ventricular Ca2+ currents in myocytes of mice overexpressing the cardiac β1-adrenoceptor.

Ca2+ currents (ICaL) carried by ventricular L-type Ca2+ channels (LTCC) are altered in failing hearts, and increased LTCC activity is discussed as a cause of cardiomyopathy. We have shown that lack of the inhibitory G-protein isoform Gαi3 improves cardiac outcome and survival in a murine heart-failure model of cardiac β1-adrenoceptor (β1-AR) overexpression (β1-tg), while lack of the Gαi2 isoform was detrimental in the same heart-failure model. Given the potential role of LTCC and their modulation by β-adrenergic signalling, we now analysed ventricular ICaL in β1-tg mice and in β1-tg mice lacking either Gαi2 or Gαi3. Using the patch-clamp technique, we recorded whole-cell ICaL in ventricular myocytes freshly isolated from adult mice. Compared to age-matched wild-type littermates, basal ICaL was reduced in myocytes from β1-tg mice both under basal conditions (- 8.1 ± 1.6 vs. - 5.5 ± 1.5 pA/pF) and upon β-adrenergic stimulation with 1 µM isoproterenol (- 14.3 ± 5.6 vs. - 7.4 ± 1.9 pA/pF). Lack of Gαi3 normalised basal ICaL to nearly wild-type levels (- 7.5 ± 1.6 pA/pF), while β-adrenergic response remained attenuated (- 9.5 ± 3.6 pA/pF). In contrast, the absence of Gαi2 did not restore basal ICaL (- 5.7 ± 1.8 pA/pF), but restored the β-adrenergic response of ICaL, with the difference from basal current even exceeding that in wild-type mice (- 12.2 ± 2.9 pA/pF).We propose that by restoring basal ICaL, Gαi3 deficiency might contribute to the restoration of contractility in β1-tg mice, while maintaining attenuation of the ICaL response upon β-adrenergic stimulation protects against deleterious effects mediated by enhanced β-AR signalling. In contrast, restored and even enhanced ICaL response to β-adrenergic stimulation might contribute to detrimental effects of Gαi2 deficiency observed in β1-tg mice previously.