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<p>Ca<sup>2+</sup> currents (<i>I</i><sub>CaL</sub>) carried by ventricular L-type Ca<sup>2+</sup> 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<sub>i3</sub> improves cardiac outcome and survival in a murine heart-failure model of cardiac β<sub>1</sub>-adrenoceptor (β<sub>1</sub>-AR) overexpression (β<sub>1</sub>-tg), while lack of the Gα<sub>i2</sub> 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>I</i><sub>CaL</sub> in β<sub>1</sub>-tg mice and in β<sub>1</sub>-tg mice lacking either Gα<sub>i2</sub> or Gα<sub>i3</sub>. Using the patch-clamp technique, we recorded whole-cell <i>I</i><sub>CaL</sub> in ventricular myocytes freshly isolated from adult mice. Compared to age-matched wild-type littermates, basal <i>I</i><sub>CaL</sub> was reduced in myocytes from β<sub>1</sub>-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<sub>i3</sub> normalised basal <i>I</i><sub>CaL</sub> 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<sub>i2</sub> did not restore basal <i>I</i><sub>CaL</sub> (− 5.7 ± 1.8 pA/pF), but restored the β-adrenergic response of <i>I</i><sub>CaL</sub>, 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>I</i><sub>CaL</sub>, Gα<sub>i3</sub> deficiency might contribute to the restoration of contractility in β<sub>1</sub>-tg mice, while maintaining attenuation of the <i>I</i><sub>CaL</sub> response upon β-adrenergic stimulation protects against deleterious effects mediated by enhanced β-AR signalling. In contrast, restored and even enhanced <i>I</i><sub>CaL</sub> response to β-adrenergic stimulation might contribute to detrimental effects of Gα<sub>i2</sub> deficiency observed in β<sub>1</sub>-tg mice previously.</p>

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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

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  • 发表日期：

    2025年3月31日

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  • Nour Katnahji,
  • Jan Matthes

摘要

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.