Beschreibung:
<p>Two subtypes of<tex-math>$\beta\!-\!adrenoceptors,\>\beta_1$</tex-math>and β<sub>2</sub>, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human β<sub>2</sub>-adrenoceptors survive high-expression levels, unlike mice overexpressing β<sub>1</sub>-adrenoceptors. We examined the role of inhibitory G<sub>i</sub>proteins, known to be activated by β<sub>2</sub>- but not β<sub>1</sub>-adrenoceptors, on the chronic effects of human β<sub>2</sub>-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where Gα<sub>i2</sub>, a functionally important cardiac<tex-math>$G_i\>\alpha\!-\!subunit$</tex-math>, was inactivated by targeted gene deletion. Survival of β<sub>2</sub>-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of Gα<sub>i2</sub>. Homozygous knockout/β<sub>2</sub>-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout/β<sub>2</sub>-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with β<sub>2</sub>-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout/β<sub>2</sub>-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment in vitro fully restored channel activity and enhanced channel activity in cells from homozygous Gα<sub>i2</sub>knockout animals. Cardiac Gα<sub>i3</sub>protein was increased in all Gα<sub>i2</sub>knockout mouse strains. Our results demonstrate that Gα<sub>i2</sub>takes an essential protective part in chronic signaling of overexpressed β<sub>2</sub>-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by β<sub>2</sub>-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by Gα<sub>i3</sub>. This result indicates that subtype-specific signaling of β<sub>2</sub>-adrenoreceptor functionally bifurcates at the level of G<sub>i</sub>, leading to different effects depending on the Gα isoform.</p>