| First Author | Foerster K | Year | 2003 |
| Journal | Proc Natl Acad Sci U S A | Volume | 100 |
| Issue | 24 | Pages | 14475-80 |
| PubMed ID | 14612574 | Mgi Jnum | J:125581 |
| Mgi Id | MGI:3759181 | Doi | 10.1073/pnas.1936026100 |
| Citation | Foerster K, et al. (2003) Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through beta 2-adrenoceptors. Proc Natl Acad Sci U S A 100(24):14475-80 |
| abstractText | 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 Gi 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 G alpha i2, a functionally important cardiac Gi alpha-subunit, was inactivated by targeted gene deletion. Survival of beta 2-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of G alpha 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 G alpha i2 knockout animals. Cardiac G alpha i3 protein was increased in all G alpha i2 knockout mouse strains. Our results demonstrate that G alpha 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 G alpha i3. This result indicates that subtype-specific signaling of beta 2-adrenoreceptor functionally bifurcates at the level of Gi, leading to different effects depending on the G alpha isoform. |
