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.

Abstract

Ca²⁺ currents (I_CaL) 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 Gα_i3 improves cardiac outcome and survival in a murine heart-failure model of cardiac β₁-adrenoceptor (β₁-AR) overexpression (β₁-tg), while lack of the Gα_i2 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 I_CaL in β₁-tg mice and in β₁-tg mice lacking either Gα_i2 or Gα_i3. Using the patch-clamp technique, we recorded whole-cell I_CaL in ventricular myocytes freshly isolated from adult mice. Compared to age-matched wild-type littermates, basal I_CaL 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 Gα_i3 normalised basal I_CaL 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 Gα_i2 did not restore basal I_CaL (- 5.7 ± 1.8 pA/pF), but restored the β-adrenergic response of I_CaL, 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 I_CaL, Gα_i3 deficiency might contribute to the restoration of contractility in β₁-tg mice, while maintaining attenuation of the I_CaL response upon β-adrenergic stimulation protects against deleterious effects mediated by enhanced β-AR signalling. In contrast, restored and even enhanced I_CaL response to β-adrenergic stimulation might contribute to detrimental effects of Gα_i2 deficiency observed in β₁-tg mice previously.