Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through β2-adrenoceptors

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