Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through beta 2-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 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.
Foerster
Katharina
K
Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
Groner
Ferdi
F
Matthes
Jan
J
Koch
Walter J
WJ
Birnbaumer
Lutz
L
Herzig
Stefan
S
D000818:Animals; D001483:Base Sequence; D015220:Calcium Channels / Q000378:metabolism; D004247:DNA / Q000235:genetics; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D015220:Calcium Channels; D011518:Proto-Oncogene Proteins; D018343:Receptors, Adrenergic, beta-2; D004247:DNA; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse