Abstract
Ca 2+ currents ( I CaL ) carried by ventricular L-type Ca 2+ 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 β 1 -adrenoceptor (β 1 -AR) overexpression (β 1 -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 β 1 -tg mice and in β 1 -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 β 1 -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 β 1 -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 β 1 -tg mice previously.