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

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