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Medientyp:
E-Artikel
Titel:
Cardioprotection specific for the G protein G i2 in chronic adrenergic signaling through β 2 -adrenoceptors
Beteiligte:
Foerster, Katharina;
Groner, Ferdi;
Matthes, Jan;
Koch, Walter J.;
Birnbaumer, Lutz;
Herzig, Stefan
Erschienen:
Proceedings of the National Academy of Sciences, 2003
Erschienen in:Proceedings of the National Academy of Sciences
Sprache:
Englisch
DOI:
10.1073/pnas.1936026100
ISSN:
0027-8424;
1091-6490
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>
Two subtypes of β-adrenoceptors, β
<jats:sub>1</jats:sub>
and β
<jats:sub>2</jats: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
<jats:sub>2</jats:sub>
-adrenoceptors survive high-expression levels, unlike mice overexpressing β
<jats:sub>1</jats:sub>
-adrenoceptors. We examined the role of inhibitory G
<jats:sub>i</jats:sub>
proteins, known to be activated by β
<jats:sub>2</jats:sub>
- but not β
<jats:sub>1</jats:sub>
-adrenoceptors, on the chronic effects of human β
<jats:sub>2</jats:sub>
-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where Gα
<jats:sub>i2</jats:sub>
, a functionally important cardiac G
<jats:sub>i</jats:sub>
α-subunit, was inactivated by targeted gene deletion. Survival of β
<jats:sub>2</jats:sub>
-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of Gα
<jats:sub>i2</jats:sub>
. Homozygous knockout/β
<jats:sub>2</jats:sub>
-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout/β
<jats:sub>2</jats:sub>
-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with β
<jats:sub>2</jats:sub>
-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout/β
<jats:sub>2</jats:sub>
-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment
<jats:italic>in vitro</jats:italic>
fully restored channel activity and enhanced channel activity in cells from homozygous Gα
<jats:sub>i2</jats:sub>
knockout animals. Cardiac Gα
<jats:sub>i3</jats:sub>
protein was increased in all Gα
<jats:sub>i2</jats:sub>
knockout mouse strains. Our results demonstrate that Gα
<jats:sub>i2</jats:sub>
takes an essential protective part in chronic signaling of overexpressed β
<jats:sub>2</jats:sub>
-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by β
<jats:sub>2</jats:sub>
-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by Gα
<jats:sub>i3</jats:sub>
. This result indicates that subtype-specific signaling of β
<jats:sub>2</jats:sub>
-adrenoreceptor functionally bifurcates at the level of G
<jats:sub>i</jats:sub>
, leading to different effects depending on the Gα isoform.
</jats:p>